| 1. |
- Subhash, Santhilal, 1987, et al.
(författare)
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Sperm Originated Chromatin Imprints and LincRNAs in Organismal Development and Cancer
- 2020
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 23:6
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Tidskriftsartikel (refereegranskat)abstract
- Importance of sperm-derived transcripts and chromatin imprints in organismal development is poorly investigated. Here using an integrative approach, we show that human sperm transcripts are equally important as oocyte. Sperm-specific and sperm-oocyte common transcripts carry distinct chromatin structures at their promoters correlating with corresponding transcript levels in sperm. Interestingly, sperm-specific H3K4me3 patterns at the lincRNA promoters are not maintained in the germ layers and somatic tissues. However, bivalent chromatin at the sperm-specific protein-coding gene promoters is maintained throughout the development. Sperm-specific transcripts reach their peak expression during zygotic genome activation, whereas sperm-oocyte common transcripts are present during early preimplantation development but decline at the onset of zygotic genome activation. Additionally, there is an inverse correlation between sperm-specific and sperm-oocyte lincRNAs throughout the development. Sperm-lincRNAs also show aberrant activation in tumors. Overall, our observations indicate that sperm transcripts carrying chromatin imprints may play an important role in human development and cancer.
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| 2. |
- Green, Leon, et al.
(författare)
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Ancestral Sperm Ecotypes Reveal Multiple Invasions of a Non-Native Fish in Northern Europe
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- For externally fertilising organisms in the aquatic environment, the abiotic fertilisation medium can be a strong selecting force. Among bony fishes, sperm are adapted to function in a narrow salinity range. A notable exception is the family Gobiidae, where several species reproduce across a wide salinity range. The family also contains several wide-spread invasive species. To better understand how these fishes tolerate such varying conditions, we measured sperm performance in relation to salinity from a freshwater and a brackish population within their ancestral Ponto-Caspian region of the round goby, Neogobius melanostomus. These two ancestral populations were then compared to nine additional invaded sites across northern Europe, both in terms of their sperm traits and by using genomic SNP markers. Our results show clear patterns of ancestral adaptations to freshwater and brackish salinities in their sperm performance. Population genomic analyses show that the ancestral ecotypes have generally established themselves in environments that fit their sperm adaptations. Sites close to ports with intense shipping show that both outbreeding and admixture can affect the sperm performance of a population in a given salinity. Rapid adaptation to local conditions is also supported at some sites. Historical and contemporary evolution in the traits of the round goby sperm cells is tightly linked to the population and seascape genomics as well as biogeographic processes in these invasive fishes. Since the risk of a population establishing in an area is related to the genotype by environment match, port connectivity and the ancestry of the round goby population can likely be useful for predicting the species spread.
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| 3. |
- Mozzachiodi, S., et al.
(författare)
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Aborting meiosis allows recombination in sterile diploid yeast hybrids
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Hybrids are often considered evolutionary dead ends because they do not generate viable offspring. Here, the authors show that sterile yeast hybrids generate genetic diversity through meiotic-like recombination by aborting meiosis and return to asexual growth. Hybrids between diverged lineages contain novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explore to what extent an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 Saccharomyces cerevisiae and S. paradoxus diploid hybrids with different genomic structures and levels of sterility. Genome analyses of 275 clones reveal that RTG promotes recombination and generates extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination is reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially arises in regions with low local heterozygosity and near meiotic recombination hotspots. The loss-of-heterozygosity has a profound impact on sexual and asexual fitness, and enables genetic mapping of phenotypic differences in sterile lineages where linkage analysis would fail. We propose that RTG gives sterile yeast hybrids access to a natural route for genome recombination and adaptation.
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| 4. |
- Stenberg, Simon, et al.
(författare)
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Control of mitochondrial superoxide production includes programmed mtDNA deletion and restoration
- 2020
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Deletion of mitochondrial DNA in eukaryotes is mainly attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that the regulatory circuitry underlying this editing critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. Our results may therefore be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.One-Sentence SummaryGenetically controlled editing of mitochondrial DNA is an integral part of the yeast’s defenses against oxidative damage.
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| 5. |
- Wieloch, Thomas, 1979-, et al.
(författare)
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Intramolecular carbon isotope signals reflect metabolite allocation in plants
- 2022
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Ingår i: Journal of Experimental Botany. - : Oxford University Press. - 0022-0957 .- 1460-2431. ; 73:8, s. 2558-2575
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Stable isotopes at natural abundance are key tools to study physiological processes occurring outside the temporal scope of manipulation and monitoring experiments. Whole-molecule carbon isotope ratios (13C/12C) enable assessments of plant carbon uptake yet conceal information about carbon allocation. Here, we identify an intramolecular 13C/12C signal at tree-ring glucose C-5 and C-6 and develop experimentally testable theories on its origin. More specifically, we assess the potential of processes within C3 metabolism for signal introduction based (inter alia) on constraints on signal propagation posed by metabolic networks. We propose that the intramolecular signal reports carbon allocation into major metabolic pathways in actively photosynthesizing leaf cells including the anaplerotic, shikimate, and non-mevalonate pathway. We support our theoretical framework by linking it to previously reported whole-molecule 13C/12C increases in cellulose of ozone-treated Betula pendula and a highly significant relationship between the intramolecular signal and tropospheric ozone concentration. Our theory postulates a pronounced preference for leaf cytosolic triose-phosphate isomerase to catalyse the forward reaction in vivo (dihydroxyacetone phosphate to glyceraldehyde 3-phosphate). In conclusion, intramolecular 13C/12C analysis resolves information about carbon uptake and allocation enabling more comprehensive assessments of carbon metabolism than whole-molecule 13C/12C analysis.
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| 6. |
- Cheregi, Otilia, et al.
(författare)
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Transcriptome analysis reveals insights into adaptive responses of two marine microalgae species to Nordic seasons
- 2023
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Ingår i: Algal Research. - 2211-9264. ; 74
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing interest in algae-based biomass produced outdoors in natural and industrial settings for biotechnological applications. To predict the yield and biochemical composition of the biomass, it is important to understand how the transcriptome of species and strains of interest is affected by seasonal changes. Here we studied the effects of Nordic winter and summer on the transcriptome of two phytoplankton species, namely the diatom Skeletonema marinoi (Sm) and the eustigmatophyte Nannochloropsis granulata (Ng), recently identified as potentially important for biomass production on the west coast of Sweden. Cultures were grown in photobioreactors in simulated Nordic summer and winter, and the gene expression in two phases was quantified by Illumina RNA-sequencing. Five paired comparisons were made among the four conditions. Sm was overall more responsive to seasons since 70 % of the total transcriptome (14,783 genes) showed differential expression in at least one comparison as compared to 1.6 % (1403 genes) for Ng. For both species, we observed larger differences between the seasons than between the phases of the same season. In summer phase 1, Sm cells focused on photosynthesis and polysaccharide biosynthesis. Nitrate assimilation and recycling of intracellular nitrogen for protein biosynthesis were more active in summer phase 2 and throughout winter. Lipid catabolism was upregulated in winter relative to summer to supply carbon for respiration. Ng favored lipid accumulation in summer, while in winter activated different lipid remodeling pathways as compared to Sm. To cope with winter, Ng upregulated breakdown and transport of carbohydrates for energy production. Taken together, our transcriptome data reveal insights into adaptive seasonal responses of Sm and Ng important for biotechnological applications on the west coast of Sweden, but more work is required to decipher the molecular mechanisms behind these responses.
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| 7. |
- Dukic Marinkov, Emilija, 1991, et al.
(författare)
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Chloroplast magnesium transporters play essential but differential roles in maintaining magnesium homeostasis
- 2023
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Ingår i: Frontiers in Plant Science. - 1664-462X. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Magnesium (Mg2+ ) is essential for photosynthesis in the chloroplasts of land plants and algae. Being the central ion of chlorophyll, cofactor and activator of many photosynthetic enzymes including RuBisCO, magnesium-deficient plants may suffer from leaf chlorosis symptoms and retarded growth. Therefore, the chloroplast Mg2+ concentration is tightly controlled by magnesium transport proteins. Recently, three different transporters from two distinct families have been identified in the chloroplast inner envelope of the model plant Arabidopsis thaliana: MGT10, MGR8, and MGR9. Here, we assess the individual roles of these three proteins in maintaining chloroplast Mg2+ homeostasis and regulating photosynthesis, and if their role is conserved in the model green alga Chlamydomonas reinhardtii. Phylogenetic analysis and heterologous expression revealed that the CorC-like MGR8 and MGR9 transport Mg2+ by a different mechanism than the CorA-like MGT10. MGR8 and MGT10 genes are highest expressed in leaves, indicating a function in chloroplast Mg2+ transport. MGR9 is important for chloroplast function and plant adaptation in conditions of deficiency or excess of Mg2+ . Transmission electron microscopy indicated that MGT10 plays a differential role in thylakoid stacking than MGR8 and MGR9. Furthermore, we report that MGR8, MGR9, and MGT10 are involved in building up the pH gradient across the thylakoid membrane and activating photoprotection in conditions of excess light, however the mechanism has not been resolved yet. While there are no chloroplast MGR-like transporters in Chlamydomonas, we show that MRS4 is a homolog of MGT10, that is required for photosynthesis and cell growth. Taken together, our findings reveal that the studied Mg2+ transporters play essential but differential roles in maintaining chloroplast Mg2+ homeostasis.
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| 8. |
- Gollan, Peter, et al.
(författare)
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Photosynthetic and transcriptome responses to fluctuating light in Arabidopsis thylakoid ion transport triple mutant
- 2023
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Ingår i: Plant Direct. - 2475-4455. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Fluctuating light intensity challenges fluent photosynthetic electron transport in plants, inducing photoprotection while diminishing carbon assimilation and growth, and also influencing photosynthetic signaling for regulation of gene expression. Here, we employed in vivo chlorophyll-a fluorescence and P700 difference absorption measurements to demonstrate the enhancement of photoprotective energy dissipation of both photosystems in wild-type Arabidopsis thaliana after 6 h exposure to fluctuating light as compared with constant light conditions. This acclimation response to fluctuating light was hampered in a triple mutant lacking the thylakoid ion transport proteins KEA3, VCCN1, and CLCe, leading to photoinhibition of photosystem I. Transcriptome analysis revealed upregulation of genes involved in biotic stress and defense responses in both genotypes after exposure to fluctuating as compared with constant light, yet these responses were demonstrated to be largely upregulated in triple mutant already under constant light conditions compared with wild type. The current study illustrates the rapid acclimation of plants to fluctuating light, including photosynthetic, transcriptomic, and metabolic adjustments, and highlights the connection among thylakoid ion transport, photosynthetic energy balance, and cell signaling.
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| 9. |
- Molin, Mikael, 1973, et al.
(författare)
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Protein kinase A controls yeast growth in visible light
- 2020
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A wide variety of photosynthetic and non-photosynthetic species sense and respond to light, having developed protective mechanisms to adapt to damaging effects on DNA and proteins. While the biology of UV light-induced damage has been well studied, cellular responses to stress from visible light (400–700 nm) remain poorly understood despite being a regular part of the life cycle of many organisms. Here, we developed a high-throughput method for measuring growth under visible light stress and used it to screen for light sensitivity in the yeast gene deletion collection. Results: We found genes involved in HOG pathway signaling, RNA polymerase II transcription, translation, diphthamide modifications of the translational elongation factor eEF2, and the oxidative stress response to be required for light resistance. Reduced nuclear localization of the transcription factor Msn2 and lower glycogen accumulation indicated higher protein kinase A (cAMP-dependent protein kinase, PKA) activity in many light-sensitive gene deletion strains. We therefore used an ectopic fluorescent PKA reporter and mutants with constitutively altered PKA activity to show that repression of PKA is essential for resistance to visible light. Conclusion: We conclude that yeast photobiology is multifaceted and that protein kinase A plays a key role in the ability of cells to grow upon visible light exposure. We propose that visible light impacts on the biology and evolution of many non-photosynthetic organisms and have practical implications for how organisms are studied in the laboratory, with or without illumination.
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| 10. |
- Stamenković, Marija, et al.
(författare)
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Fatty acids as chemotaxonomic and ecophysiological traits in green microalgae (desmids, Zygnematophyceae, Streptophyta): A discriminant analysis approach
- 2020
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Ingår i: Phytochemistry. - : Elsevier BV. - 0031-9422. ; 170
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier Ltd Desmids (Zygnematophyceae) are a group of poorly studied green microalgae. The aim of the present study was to identify fatty acids (FAs) that could be used as biomarkers in desmids in general, and to determine FAs as traits within different ecophysiological desmid groups. FA profiles of 29 desmid strains were determined and analysed with respect to their geographic origin, trophic preference and age of cultivation. It appeared that merely FAs present in relatively large proportions such as palmitic, linoleic, α-linolenic and hexadecatrienoic acids could be used as biomarkers for reliable categorization of this microalgal group. Linear discriminant analysis applied to three a priori defined groups of desmids, revealed clear strain-specific characteristics regarding FA distribution, influenced by climate and trophic conditions at the source sites as well as by the age of culture and growth phase. Accordingly, when considering FAs for the determination of lower taxonomic ranks we recommend using the term “trait” instead of “biomarker”, as the latter designates unchangeable “fingerprint” of a specific taxon. Furthermore, despite that desmids were regarded as microalgae having stable genomes, long-term cultivation appeared to cause modifications in FA metabolic pathways, evident as a larger proportion of stearidonic acid in desmid strains cultivated over extensive time periods (>35 years).
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| 11. |
- Villanova, Valeria, et al.
(författare)
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Unveiling the ecological resilience and industrial potential of Skeletonema marinoi through mixotrophic cultivation in Nordic winter condition
- 2024
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Ingår i: Physiologia Plantarum : An International Journal for Plant Biology. - 0031-9317. ; 176:3
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Tidskriftsartikel (refereegranskat)abstract
- Mixotrophy, the concurrent use of inorganic and organic carbon in the presence of light for microalgal growth, holds ecological and industrial significance. However, it is poorly explored in diatoms, especially in ecologically relevant species like Skeletonema marinoi. This study strategically employed mixotrophic metabolism to optimize the growth of a strain of Skeletonema marinoi (Sm142), which was found potentially important for biomass production on the west coast of Sweden in winter conditions. The aim of this study was to discern the most effective organic carbon sources by closely monitoring microalgal growth through the assessment of optical density, chlorophyll a fluorescence, and biomass concentration. The impact of various carbon sources on the physiology of Sm142 was investigated using photosynthetic and respiratory parameters. The findings revealed that glycerol exhibited the highest potential for enhancing the biomass concentration of Sm142 in a multi-cultivator under the specified experimental conditions, thanks to the increase in respiration activity. Furthermore, the stimulatory effect of glycerol was confirmed at a larger scale using environmental photobioreactors simulating the winter conditions on the west coast of Sweden; it was found comparable to the stimulation by CO2-enriched air versus normal air. These results were the first evidence of the ability of Skeletonema marinoi to perform mixotrophic metabolism during the winter and could explain the ecological success of this diatom on the Swedish west coast. These findings also highlight the importance of both organic and inorganic carbon sources for enhancing biomass productivity in harsh winter conditions.
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| 12. |
- Andersson, Stefanie, 1989, et al.
(författare)
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Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity
- 2021
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Ingår i: Journal of Cell Science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 134:11
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Tidskriftsartikel (refereegranskat)abstract
- The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified Saccharomyces cerevisiae deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis. This article has an associated First Person interview with the first authors of the paper.
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| 13. |
- Eme, Laura, et al.
(författare)
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Inference and reconstruction of the heimdallarchaeial ancestry of eukaryotes
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 618:7967, s. 992-
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Tidskriftsartikel (refereegranskat)abstract
- In the ongoing debates about eukaryogenesis-the series of evolutionary events leading to the emergence of the eukaryotic cell from prokaryotic ancestors-members of the Asgard archaea play a key part as the closest archaeal relatives of eukaryotes(1). However, the nature and phylogenetic identity of the last common ancestor of Asgard archaea and eukaryotes remain unresolved(2-4). Here we analyse distinct phylogenetic marker datasets of an expanded genomic sampling of Asgard archaea and evaluate competing evolutionary scenarios using state-of-the-art phylogenomic approaches. We find that eukaryotes are placed, with high confidence, as a well-nested clade within Asgard archaea and as a sister lineage to Hodarchaeales, a newly proposed order within Heimdallarchaeia. Using sophisticated gene tree and species tree reconciliation approaches, we show that analogous to the evolution of eukaryotic genomes, genome evolution in Asgard archaea involved significantly more gene duplication and fewer gene loss events compared with other archaea. Finally, we infer that the last common ancestor of Asgard archaea was probably a thermophilic chemolithotroph and that the lineage from which eukaryotes evolved adapted to mesophilic conditions and acquired the genetic potential to support a heterotrophic lifestyle. Our work provides key insights into the prokaryote-to-eukaryote transition and a platform for better understanding the emergence of cellular complexity in eukaryotic cells.
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| 14. |
- Jagers, Peter, 1941
(författare)
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Branching Processes: A Personal Historical Perspective.
- 2020
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Ingår i: Statistical Modeling for Biological Systems: In Memory of Andrei Yakovlev. - Cham : Springer International Publishing.
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The chapter, based on an Oberwolfach talk, gives a - personally biased - sketch of the development of branching processes, from the mid 19th Century to recently, emphasizing relations to bioscience and demography, and to society and culture in general.
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| 15. |
- Panagaki, Dimitra, et al.
(författare)
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Nuclear envelope budding is a response to cellular stress.
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 118:30
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analog that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope.
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| 16. |
- García-Díaz, Carmen C., et al.
(författare)
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Plasticity of mitochondrial function safeguards phosphorylating respiration during in vitro simulation of rest-phase hypothermia
- 2023
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Ingår i: FASEB Journal. - 1530-6860. ; 37:4
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Tidskriftsartikel (refereegranskat)abstract
- Many animals downregulate body temperature to save energy when resting (rest-phase hypothermia). Small birds that winter at high latitudes have comparatively limited capacity for hypothermia and so pay large energy costs for thermoregulation during cold nights. Available evidence suggests this process is fueled by adenosine triphosphate (ATP)-dependent mechanisms. Most ATP is produced by oxidative phosphorylation in the mitochondria, but mitochondrial respiration may be lower during hypothermia because of the temperature dependence of biological processes. This can create conflict between increased organismal ATP demand and a lower mitochondrial capacity to provide it. We studied this in blood cell mitochondria of wild great tits (Parus major) by simulating rest-phase hypothermia via a 6°C reduction in assay temperature in vitro. The birds had spent the night preceding the experiment in thermoneutrality or in temperatures representing mild or very cold winter nights, but night temperatures never affected mitochondrial respiration. However, across temperature groups, endogenous respiration was 14% lower in hypothermia. This did not reflect general thermal suppression of mitochondrial function because phosphorylating respiration was unaffected by thermal state. Instead, hypothermia was associated with a threefold reduction of leak respiration, from 17% in normothermia to 4% in hypothermia. Thus, the coupling of total respiration to ATP production was 96% in hypothermia, compared to 83% in normothermia. Our study shows that the thermal insensitivity of phosphorylation combined with short-term plasticity of leak respiration may safeguard ATP production when endogenous respiration is suppressed. This casts new light on the process by which small birds endure harsh winter cold and warrants future tests across tissues in vivo.
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| 17. |
- Hua, Sansan, et al.
(författare)
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Differential contributions of the proteasome, autophagy, and chaperones to the clearance of arsenite-induced protein aggregates in yeast.
- 2022
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Ingår i: The Journal of biological chemistry. - : Elsevier BV. - 1083-351X .- 0021-9258. ; 298:12
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Tidskriftsartikel (refereegranskat)abstract
- The poisonous metalloid arsenite induces widespread misfolding and aggregation of nascent proteins invivo, and this mode of toxic action might underlie its suspected role in the pathology of certain protein misfolding diseases. Evolutionarily conserved protein quality-control systems protect cells against arsenite-mediated proteotoxicity, and herein, we systematically assessed the contribution of the ubiquitin-proteasome system, the autophagy-vacuole pathway, and chaperone-mediated disaggregation to the clearance of arsenite-induced protein aggregates in Saccharomyces cerevisiae. We show that the ubiquitin-proteasome system is the main pathway that clears aggregates formed during arsenite stress and that cells depend on this pathway for optimal growth. The autophagy-vacuole pathway and chaperone-mediated disaggregation both contribute to clearance, but their roles appear less prominent than the ubiquitin-proteasome system. Our invitro assays with purified components of the yeast disaggregating machinery demonstrated that chaperone binding to aggregates formed in the presence of arsenite is impaired. Hsp104 and Hsp70 chaperone activity was unaffected by arsenite, suggesting that this metalloid influences aggregate structure, making them less accessible for chaperone-mediated disaggregation. We further show that the defect in chaperone-mediated refolding of a model protein was abrogated in a cysteine-free version of the substrate, suggesting that arsenite directly modifies cysteines in non-native target proteins. In conclusion, our study sheds novel light on the differential contributions of protein quality-control systems to aggregate clearance and cell proliferation and extends our understanding of how these systems operate during arsenite stress.
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| 18. |
- Lorentzon, Emma, 1995, et al.
(författare)
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Effects of the toxic metals arsenite and cadmium on α-synuclein aggregation in vitro and in cells
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:21
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegen-erative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.
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| 19. |
- Tulha, Joana, et al.
(författare)
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Physical, genetic and functional interactions between the eisosome protein Pil1 and the MBOAT O-acyltransferase Gup1
- 2021
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Ingår i: FEMS Yeast Research. - : Oxford University Press (OUP). - 1567-1356 .- 1567-1364. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- The Saccharomyces cerevisiae MBOAT O-acyltransferase Gup1 is involved in many processes, including cell wall and membrane composition and integrity, and acetic acid-induced cell death. Gup1 was previously shown to interact physically with the mitochondrial membrane VDAC (Voltage-Dependent Anion Channel) protein Por1 and the ammonium transceptor Mep2. By co-immunoprecipitation, the eisosome core component Pil1 was identified as a novel physical interaction partner of Gup1. The expression of PIL1 and Pil1 protein levels were found to be unaffected by GUP1 deletion. In gup1 cells, Pil1 was distributed in dots (likely representing eisosomes) in the membrane, identically to wt cells. However, gup1 cells presented 50% less Pil1-GFP dots/eisosomes, suggesting that Gup1 is important for eisosome formation. The two proteins also interact genetically in the maintenance of cell wall integrity, and during arsenite and acetic acid exposure. We show that Δgup1 Δpil1 cells take up more arsenite than wt and are extremely sensitive to arsenite and to acetic acid treatments. The latter causes a severe apoptotic wt-like cell death phenotype, epistatically reverting the gup1 necrotic type of death. Gup1 and Pil1 are thus physically, genetically and functionally connected.
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| 20. |
- Domenzain Del Castillo Cerecer, Iván, 1991
(författare)
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A systems biology understanding of protein constraints in the metabolism of budding yeasts
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fermentation technologies, such as bread making and production of alcoholic beverages, have been crucial for development of humanity throughout history. Saccharomyces cerevisiae provides a natural platform for this, due to its capability to transform sugars into ethanol. This, and other yeasts, are now used for production of pharmaceuticals, including insulin and artemisinic acid, flavors, fragrances, nutraceuticals, and fuel precursors. In this thesis, different systems biology methods were developed to study interactions between metabolism, enzymatic capabilities, and regulation of gene expression in budding yeasts. In paper I, a study of three different yeast species (S. cerevisiae, Yarrowia lipolytica and Kluyveromyces marxianus), exposed to multiple conditions, was carried out to understand their adaptation to environmental stress. Paper II revises the use of genome-scale metabolic models (GEMs) for the study and directed engineering of diverse yeast species. Additionally, 45 GEMs for different yeasts were collected, analyzed, and tested. In paper III, GECKO 2.0, a toolbox for integration of enzymatic constraints and proteomics data into GEMs, was developed and used for reconstruction of enzyme-constrained models (ecGEMs) for three yeast species and model organisms. Proteomics data and ecGEMs were used to further characterize the impact of environmental stress over metabolism of budding yeasts. On paper IV, gene engineering targets for increased accumulation of heme in S. cerevisiae cells were predicted with an ecGEM. Predictions were experimentally validated, yielding a 70-fold increase in intracellular heme. The prediction method was systematized and applied to the production of 102 chemicals in S. cerevisiae (Paper V). Results highlighted general principles for systems metabolic engineering and enabled understanding of the role of protein limitations in bio-based chemical production. Paper VI presents a hybrid model integrating an enzyme-constrained metabolic network, coupled to a gene regulatory model of nutrient-sensing mechanisms in S. cerevisiae. This model improves prediction of protein expression patterns while providing a rational connection between metabolism and the use of nutrients from the environment. This thesis demonstrates that integration of multiple systems biology approaches is valuable for understanding the connection of cell physiology at different levels, and provides tools for directed engineering of cells for the benefit of society.
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| 21. |
- Ménard, Delphine, et al.
(författare)
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Plant biomechanics and resilience to environmental changes are controlled by specific lignin chemistries in each vascular cell type and morphotype
- 2022
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Ingår i: The Plant Cell. - : Oxford University Press. - 1040-4651 .- 1532-298X. ; 34:12, s. 4877-4896
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Tidskriftsartikel (refereegranskat)abstract
- The biopolymer lignin is deposited in the cell walls of vascular cells and is essential for long-distance water conduction and structural support in plants. Different vascular cell types contain distinct and conserved lignin chemistries, each with specific aromatic and aliphatic substitutions. Yet, the biological role of this conserved and specific lignin chemistry in each cell type remains unclear. Here, we investigated the roles of this lignin biochemical specificity for cellular functions by producing single cell analyses for three cell morphotypes of tracheary elements, which all allow sap conduction but differ in their morphology. We determined that specific lignin chemistries accumulate in each cell type. Moreover, lignin accumulated dynamically, increasing in quantity and changing in composition, to alter the cell wall biomechanics during cell maturation. For similar aromatic substitutions, residues with alcohol aliphatic functions increased stiffness whereas aldehydes increased flexibility of the cell wall. Modifying this lignin biochemical specificity and the sequence of its formation impaired the cell wall biomechanics of each morphotype and consequently hindered sap conduction and drought recovery. Together, our results demonstrate that each sap-conducting vascular cell type distinctly controls their lignin biochemistry to adjust their biomechanics and hydraulic properties to face developmental and environmental constraints.
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| 22. |
- Petersen, Gitte, et al.
(författare)
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Genes from oxidative phosphorylation complexes II-V and two dual-function subunits of complex I are transcribed in Viscum album despite absence of the entire mitochondrial holo-complex I
- 2022
-
Ingår i: Mitochondrion. - : Elsevier BV. - 1567-7249 .- 1872-8278. ; 62, s. 1-12
-
Tidskriftsartikel (refereegranskat)abstract
- Mistletoes (Viscum) and close relatives are unique among flowering plants in having a drastically altered electron transport chain. Lack of complex I genes has previously been reported for the mitochondrial genome, and here we report an almost complete absence of nuclear-encoded complex I genes in the transcriptome of Viscum album. Compared to Arabidopsis with approximately 40 nuclear complex I genes, we recover only transcripts of two dual-function genes: gamma carbonic anhydrase and L-galactono-1,4-lactone dehydrogenase. The complement of genes belonging to complexes II–V of the oxidative phosphorylation pathway appears to be in accordance with other vascular plants. Additionally, transcripts encoding alternative NAD(P)H dehydrogenases and alternative oxidase were found. Despite sequence divergence, structural modeling suggests that the encoded proteins are structurally conserved. Complex I loss is a special feature in Viscum species and relatives, as all other parasitic flowering plants investigated to date seem to have a complete OXPHOS system. Hence, Viscum offers a unique system for specifically investigating molecular consequences of complex I absence, such as the role of complex I subunits involved in secondary functions.
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| 23. |
- Ulmefors, Hanna, et al.
(författare)
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Formation of Supported Lipid Bilayers Derived from Vesicles of Various Compositional Complexity on Conducting Polymer/Silica Substrates
- 2021
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 37:18, s. 5494-5505
-
Tidskriftsartikel (refereegranskat)abstract
- Supported lipid bilayers (SLBs) serve important roles as minimalistic models of cellular membranes in multiple diagnostic and pharmaceutical applications as well as in the strive to gain fundamental insights about their complex biological function. To further expand the utility of SLBs, there is a need to go beyond simple lipid compositions to thereby better mimic the complexity of native cell membranes, while simultaneously retaining their compatibility with a versatile range of analytical platforms. To meet this demand, we have in this work explored SLB formation on PEDOT:PSS/silica nanoparticle composite films and mesoporous silica films, both capable of transporting ions to an underlying conducting PEDOT:PSS film. The SLB formation process was evaluated by using the quartz crystal microbalance with dissipation (QCM-D) monitoring, total internal reflection fluorescence (TIRF) microscopy, and fluorescence recovery after photobleaching (FRAP) for membranes made of pure synthetic lipids with or without the reconstituted membrane protein β-secretase 1 (BACE1) as well as cell-derived native lipid vesicles containing overexpressed BACE1. The mesoporous silica thin film was superior to the PEDOT:PSS/silica nanoparticle composite, providing successful formation of bilayers with high lateral mobility and low defect density even for the most complex native cell membranes.
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| 24. |
- Villanova, Valeria, et al.
(författare)
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Mixotrophy in diatoms: Molecular mechanism and industrial potential.
- 2021
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Ingår i: Physiologia plantarum. - : Wiley. - 1399-3054 .- 0031-9317. ; 173:2, s. 603-611
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Forskningsöversikt (refereegranskat)abstract
- Diatoms are microalgae well known for their high variability and high primary productivity, being responsible for about 20% of the annual global carbon fixation. Moreover, they are interesting as potential feedstocks for the production of biofuels and high-value lipids and carotenoids. Diatoms exhibit trophic flexibility and, under certain conditions, they can grow mixotrophically by combing photosynthesis and respiration. So far, only a few species of diatoms have been tested for their mixotrophic metabolism; in some cases, they produced more biomass and with higher lipid content when grown under this condition. Phaeodactylum tricornutum is the most studied diatom species for its mixotrophic metabolism due to available genome sequence and molecular tools. However, studies in additional species are needed to better understand the conservation of this process in diatoms and its potential in industrial applications. Here, we describe the photosynthetic and respiratory pathways involved in mixotrophy and provide an overview of the trophic variability in diatoms. This review also highlights promising areas of industrial applications for diatoms when cultivated under mixotrophy.
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| 25. |
- Zaghlool, Ammar, 1980-, et al.
(författare)
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Characterization of the nuclear and cytosolic transcriptomes in human brain tissue reveals new insights into the subcellular distribution of RNA transcripts
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Transcriptome analysis has mainly relied on analyzing RNA sequencing data from whole cells, overlooking the impact of subcellular RNA localization and its influence on our understanding of gene function, and interpretation of gene expression signatures in cells. Here, we separated cytosolic and nuclear RNA from human fetal and adult brain samples and performed a comprehensive analysis of cytosolic and nuclear transcriptomes. There are significant differences in RNA expression for protein-coding and lncRNA genes between cytosol and nucleus. We show that transcripts encoding the nuclear-encoded mitochondrial proteins are significantly enriched in the cytosol compared to the rest of protein-coding genes. Differential expression analysis between fetal and adult frontal cortex show that results obtained from the cytosolic RNA differ from results using nuclear RNA both at the level of transcript types and the number of differentially expressed genes. Our data provide a resource for the subcellular localization of thousands of RNA transcripts in the human brain and highlight differences in using the cytosolic or the nuclear transcriptomes for expression analysis.
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| 26. |
- Benktander, John, et al.
(författare)
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Stress impairs skin barrier function and induces α2-3 linked n-acetylneuraminic acid and core 1 o-glycans on skin mucins in atlantic salmon, salmo salar
- 2021
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:3
-
Tidskriftsartikel (refereegranskat)abstract
- © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The skin barrier consists of mucus, primarily comprising highly glycosylated mucins, and the epithelium. Host mucin glycosylation governs interactions with pathogens and stress is associated with impaired epithelial barrier function. We characterized Atlantic salmon skin barrier function during chronic stress (high density) and mucin O-glycosylation changes in response to acute and chronic stress. Fish held at low (LD: 14–30 kg/m3) and high densities (HD: 50-80 kg/m3) were subjected to acute stress 24 h before sampling at 17 and 21 weeks after start of the experiment. Blood parameters indicated primary and secondary stress responses at both sampling points. At the second sampling, skin barrier function towards molecules was reduced in the HD compared to the LD group (Papp mannitol; p < 0.01). Liquid chromatography–mass spectrometry revealed 81 O-glycan structures from the skin. Fish subjected to both chronic and acute stress had an increased proportion of large O-glycan structures. Overall, four of the O-glycan changes have potential as indicators of stress, especially for the combined chronic and acute stress. Stress thus impairs skin barrier function and induces glycosylation changes, which have potential to both affect interactions with pathogens and serve as stress indicators.
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| 27. |
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| 28. |
- Dukic, Emilija, et al.
(författare)
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The Arabidopsis thylakoid chloride channel ClCe regulates ATP availability for light-harvesting complex II protein phosphorylation
- 2022
-
Ingår i: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Coping with changes in light intensity is challenging for plants, but well-designed mechanisms allow them to acclimate to most unpredicted situations. The thylakoid K+/H+ antiporter KEA3 and the voltage-dependent Cl− channel VCCN1 play important roles in light acclimation by fine-tuning electron transport and photoprotection. Good evidence exists that the thylakoid Cl− channel ClCe is involved in the regulation of photosynthesis and state transitions in conditions of low light. However, a detailed mechanistic understanding of this effect is lacking. Here we report that the ClCe loss-of-function in Arabidopsis thaliana results in lower levels of phosphorylated light-harvesting complex II (LHCII) proteins as well as lower levels of the photosystem I-LHCII complexes relative to wild type (WT) in low light conditions. The phosphorylation of the photosystem II core D1/D2 proteins was less affected either in low or high light conditions. In low light conditions, the steady-state levels of ATP synthase conductivity and of the total proton flux available for ATP synthesis were lower in ClCe loss-of-function mutants, but comparable to WT at standard and high light intensity. As a long-term acclimation strategy, expression of the ClCe gene was upregulated in WT plants grown in light-limiting conditions, but not in WT plants grown in standard light even when exposed for up to 8 h to low light. Taken together, these results suggest a role of ClCe in the regulation of the ATP synthase activity which under low light conditions impacts LHCII protein phosphorylation and state transitions.
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| 29. |
- Ebrahimi, Mahsa, 1985-, et al.
(författare)
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Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway
- 2021
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 10:11
-
Tidskriftsartikel (refereegranskat)abstract
- Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.
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| 30. |
- Ezzedine, Jade A., et al.
(författare)
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Adaptive traits of cysts of the snow alga Sanguina nivaloides unveiled by 3D subcellular imaging
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- Sanguina nivaloides is the main alga forming red snowfields in high mountains and Polar Regions. It is non-cultivable. Analysis of environmental samples by X-ray tomography, focused-ion-beam scanning-electron-microscopy, physicochemical and physiological characterization reveal adaptive traits accounting for algal capacity to reside in snow. Cysts populate liquid water at the periphery of ice, are photosynthetically active, can survive for months, and are sensitive to freezing. They harbor a wrinkled plasma membrane expanding the interface with environment. Ionomic analysis supports a cell efflux of K+, and assimilation of phosphorus. Glycerolipidomic analysis confirms a phosphate limitation. The chloroplast contains thylakoids oriented in all directions, fixes carbon in a central pyrenoid and produces starch in peripheral protuberances. Analysis of cells kept in the dark shows that starch is a short-term carbon storage. The biogenesis of cytosolic droplets shows that they are loaded with triacylglycerol and carotenoids for long-term carbon storage and protection against oxidative stress.
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| 31. |
- Gebremariam, Hanna Gebreegziabher, 1987-
(författare)
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Role of lactobacilli in Helicobacter pylori pathogenesis and host cell responses
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori is well adapted to the harsh environment of the human stomach, allowing it to persistently colonize the gastric mucosa of at least 50% of the global population for decades. Long-term colonization induces chronic inflammation that can eventually lead to development of peptic ulcer and gastric cancer. The interaction between host, bacterial and environmental factors are crucial for the pathogenesis of H. pylori. In contrast, Lactobacillus species are members of the human microbiota and act as a first line of defense against pathogens. However, the underlying mechanisms behind lactobacilli-mediated pathogen inhibition still need further investigation.This thesis focuses on understanding the interplay between commensal and pathogenic bacteria with the human host. In Paper I, we investigated the effect of different Lactobacillus strains on the initial attachment of H. pylori to gastric epithelial cells and found that certain Lactobacillus strains can prevent the adhesion of the pathogen by decreasing the expression of SabA. In Paper II, the anti-inflammatory activity of Lactobacillus strains against H. pylori-induced production of proinflammatory cytokines was explored. We demonstrated the ability of L. gasseri Kx110A1 to reduce the level of TNF and IL-6 in human macrophages through suppression of ADAM17, a metalloproteinase responsible for releasing transmembrane proteins. Lactobacilli-mediated inhibition of these cytokines was not H. pylori-specific, suggesting a general anti-inflammatory property of L. gasseri Kx110A1. In Paper III, we characterized the role of sortase-dependent proteins in L. gasseri Kx110A1. We showed that the deletion of sortase A in lactobacilli resulted in the reduction of auto-aggregation and attachment to host gastric epithelial cells. Moreover, sortase A mutant lactobacilli were not effective in preventing H. pylori initial adherence. Finally, in Paper IV, we showed that lactate can affect the expression of H. pylori adherence genes and the production of bacterial-induced proinflammatory cytokines.
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| 32. |
- Ghirmai, Semhar, 1993
(författare)
-
Prevention of hemolysis as a novel strategy to limit hemoglobin-mediated lipid oxidation in fish - towards a more sustainable use of fish raw materials
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hemoglobin (Hb) has been recognized as a main pro-oxidant in fish, causing fast and intense lipid oxidation. This thesis explores the hypothesis that maintaining red blood cells (RBCs) intact for an extended time during fish processing could delay Hb-mediated lipid oxidation. The aims were to (i) unravel how selected endogenous and exogenous parameters affect fish RBC-stability, (ii) confirm the relation between hemolysis and lipid oxidation and (iii), evaluate antioxidative strategies to prevent oxidation caused by released Hb. In Study I, washed and resuspended trout RBCs (wr-RBC) and whole trout blood (WB) were used to study how temperature, salinity and mechanic pressure affect hemolysis. Cold temperatures, 0-6 °C, and physiological saline were advantageous for the RBC stability while hyper- (3% NaCl) or hypotonic (tap water) conditions as well as simulated mechanic pressure hemolysis. Study II revealed that typical post-mortem pH’s, 6.4 and 6.8, yielded a higher hemolysis rate of wr-RBCs compared to pH 7.2-8.0, and stimulated lipid oxidation of the RBC membrane. Similarly, in RBC-spiked washed cod mince (WCM), pH 6.4/6.8 stimulated both lipid oxidation and hemolysis compared to pH 7.2/7.6 (Study III). Hb-analyses of the soluble phase revealed that only low levels of released Hb (7.1 µM) were needed to initiate lipid oxidation at pH 6.4-6.8, which was not the case at high pH, even when >50% of the Hb was in the metHb form. In experiments with wr-RBCs, re-addition of blood plasma (12-75% v/w) largely increased the RBC stability (Study I-II). The stabilizing effect was partly ascribed to glucose, albumin, and ascorbic acid (AA). Adding blood plasma to the RBC-spiked WCM system 3% (v/w), delayed the onset of lipid oxidation at pH 6.8 with 3-4 days without delaying hemolysis; the latter most likely due to the high plasma dilution. To clarify the effect of hemolysis on WCM lipid oxidation, different ratios of intact and lysed RBCs were added to a WCM system at pH 6.8 (Study III). Samples with 25-100% lysed RBCs oxidized rapidly within the first day of storage, whereas the sample with 100% intact RBCs provided a 1-day delay in the onset of lipid oxidation. Further, the sample with initially fully intact RBCs resulted in 59.5± 2.9% and 48.1± 2.9% reduced maximum peroxide value (PV) and thiobarbituric acid reactive substances (TBARS), respectively. Short pre-incubation of herring co-products in 0.9% NaCl removed 6.6-18.0% of their Hb and slightly reduced the intensity of TBARS development during ice storage of the minced product, compared to pre-incubation in tap water or no pre-incubation (Study IV). Refrigerated storage of herring co-products while submerged in tap water, 0.9% NaCl or phosphate buffered saline (PBS) (pH 6.5 or 7.5) also reduced the lipid oxidation intensity compared to air-storage; however, without any effect from pH or salinity. When adding the commercial antioxidant mixture Duralox-MANC to the pre-incubation or submerging solutions (2% vs 0.5%) the lipid oxidation lag phase was largely prolonged; e.g., from < 1 day in controls to >6 days. Direct fortification of minced herring co-products with 0.5 % Duralox-MANC confirmed its antioxidative efficiency as lipid stability was prolonged from <1 day to >8 days. Altogether, this thesis confirmed that delaying hemolysis can be a route to delay lipid oxidation. It also revealed that current conditions used in the early handling/processing of fish, such as subjection to crowding, pumping, refrigerated sea water (RSW)-storage or tap water rinsing do not favor RBC stability and call for adjustments to limit hemolysis; and thereby Hb-mediated lipid oxidation. Intact RBCs, presence of blood plasma and elevated pH’s delayed lipid oxidation in a WCM system, providing an important window of time which could allow for better utilization of blood-rich fish raw materials currently leaving the food chain. To further enhance the lipid stability of such materials, subjecting them to rosemary-derived antioxidants via pre-incubation, submerging or direct addition is recommended. Results presented can contribute to an increased robustness of our global food systems towards unprecedented challenges such as pandemics, war, and climate threats. They also contribute to the ongoing dietary protein shift in which aquatic foods as small pelagic fish and fish rest raw materials have an immense potential if correctly preserved by updated procedures.
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| 33. |
- Gorreja, Frida, et al.
(författare)
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The potential role of adherence factors in probiotic function in the gastrointestinal tract of adults and pediatrics: a narrative review of experimental and human studies.
- 2022
-
Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0984 .- 1949-0976. ; 14:1
-
Forskningsöversikt (refereegranskat)abstract
- Numerous studies point to the important role of probiotic bacteria in gastrointestinal health. Probiotics act through mechanisms affecting enteric pathogens, epithelial barrier function, immune signaling, and conditioning of indigenous microbiota. Once administered, probiotics reach the gastrointestinal tract and interact with the host through bacterial surface molecules, here called adhesion factors, which are either strain- or specie-specific. Probiotic adhesion, through structural adhesion factors, is a mechanism that facilitates persistence within the gastrointestinal tract and triggers the initial host responses. Thus, an understanding of specific probiotic adhesion mechanisms could predict how specific probiotic strains elicit benefits and the potential of adherence factors as a proxy to predict probiotic function. This review summarizes the present understanding of probiotic adherence in the gastrointestinal tract. It highlights the bacterial adhesion structure types, their molecular communication with the host and the consequent impact on intestinal diseases in both adult and pediatric populations. Finally, we discuss knockout/isolation studies as direct evidence for adhesion factors conferring anti-inflammatory and pathogen inhibition properties to a probiotic.What is known: Probiotics can be used to treat clinical conditions.Probiotics improve dysbiosis and symptoms.Clinical trials may not confirm in vitro and animal studies.What is new: Adhesion structures may be important for probiotic function.Need to systematically determine physical characteristics of probiotics before selecting for clinical trials.Probiotics may be genetically engineered to add to clinical efficacy.
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| 34. |
- Gupta, G., et al.
(författare)
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Exploiting Mass Spectrometry to Unlock the Mechanism of Nanoparticle-Induced Inflammasome Activation
- 2023
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Ingår i: Acs Nano. - : AMER CHEMICAL SOC. - 1936-0851 .- 1936-086X. ; 17:17, s. 17451-17467
-
Tidskriftsartikel (refereegranskat)abstract
- Nanoparticles (NPs) elicit sterile inflammation, but the underlying signaling pathways are poorly understood. Here, we report that human monocytes are particularly vulnerable to amorphous silica NPs, as evidenced by single-cell-based analysis of peripheral blood mononuclear cells using cytometry by time-of-flight (CyToF), while silane modification of the NPs mitigated their toxicity. Using human THP-1 cells as a model, we observed cellular internalization of silica NPs by nanoscale secondary ion mass spectrometry (nanoSIMS) and this was confirmed by transmission electron microscopy. Lipid droplet accumulation was also noted in the exposed cells. Furthermore, time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed specific changes in plasma membrane lipids, including phosphatidylcholine (PC) in silica NP-exposed cells, and subsequent studies suggested that lysophosphatidylcholine (LPC) acts as a cell autonomous signal for inflammasome activation in the absence of priming with a microbial ligand. Moreover, we found that silica NPs elicited NLRP3 inflammasome activation in monocytes, whereas cell death transpired through a non-apoptotic, lipid peroxidation-dependent mechanism. Together, these data further our understanding of the mechanism of sterile inflammation.
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| 35. |
- Han, Shunhua, et al.
(författare)
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Transposable element profiles reveal cell line identity and loss of heterozygosity in Drosophila cell culture.
- 2021
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Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 219:2
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Tidskriftsartikel (refereegranskat)abstract
- Cell culture systems allow key insights into biological mechanisms yet suffer from irreproducible outcomes in part because of cross-contamination or mislabeling of cell lines. Cell line misidentification can be mitigated by the use of genotyping protocols, which have been developed for human cell lines but are lacking for many important model species. Here, we leverage the classical observation that transposable elements (TEs) proliferate in cultured Drosophila cells to demonstrate that genome-wide TE insertion profiles can reveal the identity and provenance of Drosophila cell lines. We identify multiple cases where TE profiles clarify the origin of Drosophila cell lines (Sg4, mbn2, and OSS_E) relative to published reports, and also provide evidence that insertions from only a subset of long-terminal repeat retrotransposon families are necessary to mark Drosophila cell line identity. We also develop a new bioinformatics approach to detect TE insertions and estimate intra-sample allele frequencies in legacy whole-genome sequencing data (called ngs_te_mapper2), which revealed loss of heterozygosity as a mechanism shaping the unique TE profiles that identify Drosophila cell lines. Our work contributes to the general understanding of the forces impacting metazoan genomes as they evolve in cell culture and paves the way for high-throughput protocols that use TE insertions to authenticate cell lines in Drosophila and other organisms.
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| 36. |
- Hildebrandt, Franziska, 1994-, et al.
(författare)
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scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics
- 2023
-
Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells and macrophages are integral parts of the innate immune system and gatekeepers against infection. The protozoan pathogen, Toxoplasma gondii, is known to hijack host immune cells and modulate their immune response, making it a compelling model to study host-pathogen interactions. Here we utilize single cell Dual RNA-seq to parse out heterogeneous transcription of mouse bone marrow-derived dendritic cells (BMDCs) infected with two distinct genotypes of T. gondii parasites, over multiple time points post infection. We show that the BMDCs elicit differential responses towards T. gondii infection and that the two parasite lineages distinctly manipulate subpopulations of infected BMDCs. Co-expression networks define host and parasite genes, with implications for modulation of host immunity. Integrative analysis validates previously established immune pathways and additionally, suggests novel candidate genes involved in host-pathogen interactions. Altogether, this study provides a comprehensive resource for characterizing host-pathogen interplay at high-resolution.
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| 37. |
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| 38. |
- Keuenhof, Katharina, 1994, et al.
(författare)
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Large organellar changes occur during mild heat shock in yeast
- 2021
-
Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 135:5
-
Tidskriftsartikel (refereegranskat)abstract
- When the temperature is increased, the heat shock response is activated to protect the cellular environment. The transcriptomics and proteomics of this process are intensively studied, while information about how the cell responds structurally to heat stress is mostly lacking. Here, Saccharomyces cerevisiae were subjected to a mild continuous heat shock (38°C) and intermittently cryo-immobilized for electron microscopy. Through measuring changes in all distinguishable organelle numbers, sizes, and morphologies in over 2100 electron micrographs a major restructuring of the cell's internal architecture during the progressive heat shock was revealed. The cell grew larger but most organelles within it expanded even more, shrinking the volume of the cytoplasm. Organelles responded to heat shock at different times, both in terms of size and number, and adaptations of certain organelles' morphology (such as the vacuole), were observed. Multivesicular bodies grew to almost 170% in size, indicating a previously unknown involvement in the heat shock response. A previously undescribed electron translucent structure accumulated close to the plasma membrane. This all-encompassing approach provides a detailed chronological progression of organelle adaptation throughout the cellular heat-stress response.
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| 39. |
- Kohler, Verena, 1992-, et al.
(författare)
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Closing the gap : membrane contact sites in the regulation of autophagy
- 2020
-
Ingår i: Cells. - : MDPI. - 2073-4409. ; 9:5, s. 1184-1184
-
Forskningsöversikt (refereegranskat)abstract
- In all eukaryotic cells, intracellular organization and spatial separation of incompatible biochemical processes is established by individual cellular subcompartments in form of membrane-bound organelles. Virtually all of these organelles are physically connected via membrane contact sites (MCS), allowing interorganellar communication and a functional integration of cellular processes. These MCS coordinate the exchange of diverse metabolites and serve as hubs for lipid synthesis and trafficking. While this of course indirectly impacts on a plethora of biological functions, including autophagy, accumulating evidence shows that MCS can also directly regulate autophagic processes. Here, we focus on the nexus between interorganellar contacts and autophagy in yeast and mammalian cells, highlighting similarities and differences. We discuss MCS connecting the ER to mitochondria or the plasma membrane, crucial for early steps of both selective and non-selective autophagy, the yeast-specific nuclear–vacuolar tethering system and its role in microautophagy, the emerging function of distinct autophagy-related proteins in organellar tethering as well as novel MCS transiently emanating from the growing phagophore and mature autophagosome.
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| 40. |
- Kosek, David M, et al.
(författare)
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Efficient 3′-pairing renders microRNA targeting less sensitive to mRNA seed accessibility
- 2023
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 51:20, s. 11162-11177
-
Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are short RNAs that post-transcriptionally regulate gene expression by binding to specific sites in mRNAs. Site recognition is primarily mediated by the seed region (nucleotides g2–g8 in the miRNA), but pairing beyond the seed (3′-pairing) is important for some miRNA:target interactions. Here, we use SHAPE, luciferase reporter assays and transcriptomics analyses to study the combined effect of 3′-pairing and secondary structures in mRNAs on repression efficiency. Using the interaction between miR-34a and its SIRT1 binding site as a model, we provide structural and functional evidence that 3′-pairing can compensate for low seed-binding site accessibility, enabling repression of sites that would otherwise be ineffective. We show that miRNA 3′-pairing regions can productively base-pair with nucleotides far upstream of the seed-binding site and that both hairpins and unstructured bulges within the target site are tolerated. We use SHAPE to show that sequences that overcome inaccessible seed-binding sites by strong 3′-pairing adopt the predicted structures and corroborate the model using luciferase assays and high-throughput modelling of 8177 3′-UTR targets for six miRNAs. Finally, we demonstrate that PHB2, a target of miR-141, is an inaccessible target rescued by efficient 3′-pairing. We propose that these results could refine predictions of effective target sites.
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| 41. |
- Malak, Monika, 1993, et al.
(författare)
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Monitoring calcium-induced epidermal differentiation in vitro using multiphoton microscopy
- 2020
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Ingår i: Journal of Biomedical Optics. - 1083-3668 .- 1560-2281. ; 25:7, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- SIGNIFICANCE: Research in tissue engineering and in vitro organ formation has recently intensified. To assess tissue morphology, the method of choice today is restricted primarily to histology. Thus novel tools are required to enable noninvasive, and preferably label-free, three-dimensional imaging that is more compatible with futuristic organ-on-a-chip models. AIM: We investigate the potential for using multiphoton microscopy (MPM) as a label-free in vitro approach to monitor calcium-induced epidermal differentiation. APPROACH: In vitro epidermis was cultured at the air-liquid interface in varying calcium concentrations. Morphology and tissue architecture were investigated using MPM based on visualizing cellular autofluorescence. RESULTS: Distinct morphologies corresponding to epidermal differentiation were observed. In addition, Ca2+-induced effects could be distinguished based on the architectural differences in stratification in the tissue cultures. CONCLUSIONS: Our study shows that MPM based on cellular autofluorescence enables visualization of Ca2+-induced differentiation in epidermal skin models in vitro. The technique has potential to be further adapted as a noninvasive, label-free, and real-time tool to monitor tissue regeneration and organ formation in vitro.
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| 42. |
- Powers, Christopher, et al.
(författare)
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Two canonically aerobic foraminifera express distinct peroxisomal and mitochondrial metabolisms
- 2022
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Certain benthic foraminifera thrive in marine sediments with low or undetectable oxygen. Potential survival avenues used by these supposedly aerobic protists include fermentation and anaerobic respiration, although details on their adaptive mechanisms remain elusive. To better understand the metabolic versatility of foraminifera, we studied two benthic species that thrive in oxygen-depleted marine sediments. Here we detail, via transcriptomics and metatranscriptomics, differential gene expression of Nonionella stella and Bolivina argentea, collected from Santa Barbara Basin, California, USA, in response to varied oxygenation and chemical amendments. Organelle-specific metabolic reconstructions revealed these two species utilize adaptable mitochondrial and peroxisomal metabolism. N. stella, most abundant in anoxia and characterized by lack of food vacuoles and abundance of intracellular lipid droplets, was predicted to couple the putative peroxisomal beta-oxidation and glyoxylate cycle with a versatile electron transport system and a partial TCA cycle. In contrast, B. argentea, most abundant in hypoxia and contains food vacuoles, was predicted to utilize the putative peroxisomal gluconeogenesis and a full TCA cycle but lacks the expression of key beta-oxidation and glyoxylate cycle genes. These metabolic adaptations likely confer ecological success while encountering deoxygenation and expand our understanding of metabolic modifications and interactions between mitochondria and peroxisomes in protists.
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| 43. |
- Quintana-Hayashi, Macarena P, et al.
(författare)
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Brachyspira species avidity to colonic mucins from pigs with and without brachyspira hyodysenteriae infection is species specific and varies between strains
- 2021
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 89:12
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Tidskriftsartikel (refereegranskat)abstract
- Brachyspira hyodysenteriae is commonly associated with swine dysentery (SD), a disease that has an economic impact on the swine industry. B. hyodysenteriae infection results in changes to the colonic mucus niche with massive mucus induction, which substantially increases the number of B. hyodysenteriae binding sites in the mucus. We previously determined that a B. hyodysenteriae strain binds to colon mucins in a manner that differs between pigs and mucin types. Here, we investigated if adhesion to mucins is a trait observed across a broad set of B. hyodysenteriae strains and isolates and furthermore at a genus level (B. innocens, B. pilosicoli, B. murdochii, B. hampsonii, and B. intermedia strains). Our results show that binding to mucins appears to be specific to B. hyodysenteriae, and within this species, the binding ability to mucins varies between strains/isolates, increases for mucins from pigs with SD, and is associated with sialic acid epitopes on mucins. Infection with B. hyodysenteriae strain 8dII results in mucin glycosylation changes in the colon, including a shift in sialic acid-containing structures. Thus, we demonstrate through hierarchical cluster analysis and orthogonal projections to latent structures discriminant analysis (OPLS-DA) models of the relative abundances of sialic acid-containing glycans that sialic acid-containing structures in the mucin O-glycome are good predictors of B. hyodysenteriae strain 8dII infection in pigs. The results emphasize the role of sialic acids in governing B. hyodysenteriae interactions with its host, which may open perspectives for therapeutic strategies.
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| 44. |
- Ross, Emily C., 1991-
(författare)
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Transmigration of Toxoplasma gondii across biological barriers
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Toxoplasma gondii is an obligate intracellular parasite that can likely infect all warm-blooded vertebrates, with estimates of up to 30% of the global human population being infected. Although infection with T. gondii is usually asymptomatic or mild, in immunocompromised individuals infection can lead to lethal toxoplasmic encephalitis. Infection acquired during pregnancy can also lead to serious ocular or neurological damage and even death of the foetus. Following ingestion, the parasite is able to cross the first biological barrier it encounters, the gut epithelium and convert to the rapidly replicating tachyzoite stage. It can then disseminate throughout the body of the host, eventually reaching sites such as the brain, after crossing the blood-brain barrier (BBB). Previous findings have shown that T. gondii can use leukocytes, such as dendritic cells (DCs), for dissemination via a “Trojan horse”-type mechanism, but how T. gondii then crosses restrictive barriers such as the BBB is still not fully understood. The overall objective of this work has been to investigate how T. gondii crosses biological barriers and how infection impacts host cell signalling.In paper I we demonstrate that T. gondii can cross polarised cell monolayers without significantly perturbing barrier integrity. Reduced phosphorylation of focal adhesion kinase (FAK) was observed in cell monolayers upon T. gondii challenge, and inhibition or gene silencing of FAK (Ptk2) facilitated transmigration of T. gondii across polarised cell monolayers. In paper II we found that upon T. gondii infection of DCs, secreted TIMP-1 induces hypermotility by activating β1 integrin-FAK signalling through interactions with CD63. In paper III we show that T. gondii can cross polarised endothelial cell monolayers inside DCs. We also report that parasitised DCs on endothelium do not display a hypermotile phenotype, switching to integrin-dependent motility. Blockade of β1 and β2 integrins or ICAM-1, and gene silencing of β1 (Itgb1) or talin (Tln1) restored infected-DC motility, and reduced the frequency of transmigration of T. gondii-challenged DCs across endothelium. In paper IV we demonstrate that, shortly after T. gondii inoculation in mice, parasites mainly localised to cortical capillaries of the brain. Early invasion to the brain parenchyma occurred in absence of a significant increase in BBB permeability, perivascular leukocyte cuffs or haemorrhage. Further, pharmacological inhibition or endothelial cell-specific knockout of FAK facilitated parasite transmigration to the brain parenchyma. In paper V we report that DCs challenged with type II T. gondii transmigrate across polarised endothelial cell monolayers at a higher frequency than type I T. gondii, while type I infected DCs exhibited increased migratory velocities on endothelium. We also show that T. gondii-induced upregulation of ICAM-1 in DCs is genotype-dependent, and requires the T. gondii secreted effector GRA15. Finally, gene silencing of leukocyte ICAM-1 (Icam-1) or deletion of T. gondii GRA15 reduced transmigration across endothelial cell monolayers.In summary, the work in this thesis provides novel insights into how T. gondii can potentially cross biological barriers on its journey to the brain. We find that T. gondii can cross polarised monolayers both as free parasites and using DCs as a “Trojan horse”, and identify new ways in which T. gondii can alter host cell dynamics to benefit its own dissemination.
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| 45. |
- Shashkova, Sviatlana, 1987, et al.
(författare)
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Correlating single-molecule characteristics of the yeast aquaglyceroporin Fps1 with environmental perturbations directly in living cells
- 2021
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Ingår i: Methods. - : Elsevier BV. - 1095-9130 .- 1046-2023. ; 193, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- Membrane proteins play key roles at the interface between the cell and its environment by mediating selective import and export of molecules via plasma membrane channels. Despite a multitude of studies on transmembrane channels, understanding of their dynamics directly within living systems is limited. To address this, we correlated molecular scale information from living cells with real time changes to their microenvironment. We employed super-resolved millisecond fluorescence microscopy with a single-molecule sensitivity, to track labelled molecules of interest in real time. We use as example the aquaglyceroporin Fps1 in the yeast Saccharomyces cerevisiae to dissect and correlate its stoichiometry and molecular turnover kinetics with various extracellular conditions. We show that Fps1 resides in multi tetrameric clusters while hyperosmotic and oxidative stress conditions cause Fps1 reorganization. Moreover, we demonstrate that rapid exposure to hydrogen peroxide causes Fps1 degradation. In this way we shed new light on aspects of architecture and dynamics of glycerol-permeable plasma membrane channels.
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| 46. |
- Stenberg, Simon, et al.
(författare)
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Genetically controlled mtDNA deletions prevent ROS damage by arresting oxidative phosphorylation.
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Deletion of mitochondrial DNA in eukaryotes is currently attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that this process critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication through Rtg2 and Rtg3. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. This shows that oxidative stress-induced mitochondrial impairment may be under strict regulatory control. If the results extend to human cells, the results may prove to be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease.
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| 47. |
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| 48. |
- Villanova, Valeria, et al.
(författare)
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Mixotrophy in a Local Strain of Nannochloropsis granulata for Renewable High-Value Biomass Production on the West Coast of Sweden
- 2022
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Ingår i: Marine Drugs. - : MDPI. - 1660-3397. ; 20:7
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Tidskriftsartikel (refereegranskat)abstract
- A local strain of Nannochloropsis granulata (Ng) has been reported as the most productive microalgal strain in terms of both biomass yield and lipid content when cultivated in photobioreactors that simulate the light and temperature conditions during the summer on the west coast of Sweden. To further increase the biomass and the biotechnological potential of this strain in these conditions, mixotrophic growth (i.e., the simultaneous use of photosynthesis and respiration) with glycerol as an external carbon source was investigated in this study and compared with phototrophic growth that made use of air enriched with 1–2% CO2 . The addition of either glycerol or CO2-enriched air stimulated the growth of Ng and theproduction of high-value long-chain polyunsaturated fatty acids (EPA) as well as the carotenoid canthaxanthin. Bioassays in human prostate cell lines indicated the highest antitumoral activity for Ng extracts and fractions from mixotrophic conditions. Metabolomics detected betaine lipids specifically in the bioactive fractions, suggesting their involvement in the observed antitumoral effect. Genes related to autophagy were found to be upregulated by the most bioactive fraction, suggesting a possible therapeutic target against prostate cancer progression. Taken together, our results suggest that the local Ng strain can be cultivated mixotrophically in summer conditions on the west coast of Sweden for the production of high-value biomass containing antiproliferative compounds, carotenoids, and EPA. © 2022 by the authors.
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| 49. |
- Waszczak, Cezary, et al.
(författare)
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Synthesis and import of GDP-l-fucose into the Golgi affect plant–water relations
- 2023
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Ingår i: New Phytologist. - 0028-646X .- 1469-8137. ; 241:2, s. 747-63
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Tidskriftsartikel (refereegranskat)abstract
- Land plants evolved multiple adaptations to restrict transpiration. However, the underlying molecular mechanisms are not sufficiently understood. We used an ozone-sensitivity forward genetics approach to identify Arabidopsis thaliana mutants impaired in gas exchange regulation. High water loss from detached leaves and impaired decrease of leaf conductance in response to multiple stomata-closing stimuli were identified in a mutant of MURUS1 (MUR1), an enzyme required for GDP-l-fucose biosynthesis. High water loss observed in mur1 was independent from stomatal movements and instead could be linked to metabolic defects. Plants defective in import of GDP-l-Fuc into the Golgi apparatus phenocopied the high water loss of mur1 mutants, linking this phenotype to Golgi-localized fucosylation events. However, impaired fucosylation of xyloglucan, N-linked glycans, and arabinogalactan proteins did not explain the aberrant water loss of mur1 mutants. Partial reversion of mur1 water loss phenotype by borate supplementation and high water loss observed in boron uptake mutants link mur1 gas exchange phenotypes to pleiotropic consequences of l-fucose and boron deficiency, which in turn affect mechanical and morphological properties of stomatal complexes and whole-plant physiology. Our work emphasizes the impact of fucose metabolism and boron uptake on plant–water relations.
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| 50. |
- Yamamoto, Io, et al.
(författare)
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Telomeric double-strand DNA-binding proteins DTN-1 and DTN-2 ensure germline immortality in Caenorhabditis elegans.
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Telomeres are nucleoprotein complexes at the ends of chromosomes and are indispensable for the protection and lengthening of terminal DNA. Despite the evolutionarily conserved roles of telomeres, the telomeric double-strand DNA (dsDNA)-binding proteins have evolved rapidly. Here, we identified double-strand telomeric DNA-binding proteins (DTN-1 and DTN-2) in Caenorhabditis elegans as non-canonical telomeric dsDNA-binding proteins. DTN-1 and DTN-2 are paralogous proteins that have three putative MYB-like DNA-binding domains and bind to telomeric dsDNA in a sequence-specific manner. DTN-1 and DTN-2 form complexes with the single-strand telomeric DNA-binding proteins POT-1 and POT-2 and constitutively localize to telomeres. The dtn-1 and dtn-2 genes function redundantly, and their simultaneous deletion results in progressive germline mortality, which accompanies telomere hyper-elongation and chromosomal bridges. Our study suggests that DTN-1 and DTN-2 are core shelterin components in C. elegans telomeres that act as negative regulators of telomere length and are essential for germline immortality.
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