| 1. |
- Eisele-Bürger, Anna Maria, et al.
(författare)
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Calmodulin regulates protease versus co-chaperone activity of a metacaspase
- 2023
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Ingår i: Cell Reports. - 2211-1247. ; 42:11
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Tidskriftsartikel (refereegranskat)abstract
- Metacaspases are ancestral homologs of caspases that can either promote cell death or confer cytoprotection. Furthermore, yeast (Saccharomyces cerevisiae) metacaspase Mca1 possesses dual biochemical activity: proteolytic activity causing cell death and cytoprotective, co-chaperone-like activity retarding replicative aging. The molecular mechanism favoring one activity of Mca1 over another remains elusive. Here, we show that this mechanism involves calmodulin binding to the N-terminal pro-domain of Mca1, which prevents its proteolytic activation and promotes co-chaperone-like activity, thus switching from pro-cell death to anti-aging function. The longevity-promoting effect of Mca1 requires the Hsp40 co-chaperone Sis1, which is necessary for Mca1 recruitment to protein aggregates and their clearance. In contrast, proteolytically active Mca1 cleaves Sis1 both in vitro and in vivo, further clarifying molecular mechanism behind a dual role of Mca1 as a cell-death protease versus gerontogene.
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| 2. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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Asymmetric Inheritance of Aggregated Proteins and Age Reset in Yeast Are Regulated by Vac17-Dependent Vacuolar Functions
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 16:3, s. 826-838
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Tidskriftsartikel (refereegranskat)abstract
- Age can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae, we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan. The link between damage asymmetry and vesicle trafficking can be explained by a direct interaction between aggregates and vesicles. We also show that the protein disaggregase Hsp104 interacts physically with endocytic vesicle-associated proteins, such as the dynamin-like protein, Vps1, which was also shown to be required for Vac17-dependent sequestration of protein aggregates. These data demonstrate that two physiognomies of aging-reduced endocytosis and protein aggregation-are interconnected and regulated by Vac17.
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| 3. |
- Hill, Sandra Malmgren, 1987
(författare)
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Damage Segregation and Cellular Rejuvenation in Saccharomyces cerevisiae
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The process of aging is defined as a time-dependent decline in cellular functionality, and aging is thought to have evolved as organisms were optimized for reproduction, at the cost of an imperfect repair and maintenance system. As a consequence, different kinds of dysfunctional components and damage accumulate over time. Eventually these dysfunctional components, termed aging factors, reach critical levels at which they interfere with cellular systems, causing the age-related loss of function that ultimately leads to cell death. The investment in propagation also encompasses the retention of aging factors within the progenitor cell, so that the progeny is born rejuvenated, free from damaging aging factors. The accumulation of oxidized and aggregated proteins has been established to act as aging factors in several organisms. These damaged proteins are asymmetrically distributed during cell division, a process that in yeast relies on the actin cytoskeleton and components of the cellular protein quality control (PQC) system. In my work, I have established that this asymmetric damage segregation is an active and factor-dependent process, accomplished through the actions of two interconnected systems. Mainly, sequestration of protein aggregates into certain quality control sites within the mother cell ensures the retention of damage, but cells have also evolved a process of aggregate removal so that any damage that accidentally leaks into the daughter cell is removed. This removal is achieved either by degradation or by retrograde transport of aggregates back into the mother cell. – Text removed from public version – Additionally, we found that the process of aggregate removal includes an unexpected role for the metacaspase Mca1, acting in conjunction with the proteasome and PQC system to degrade aggregated proteins. The link between protein aggregation and aging is further reinforced by our data demonstrating that altered levels of these identified AGGs affect cellular fitness and longevity.
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| 4. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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Life-span extension by a metacaspase in the yeast Saccharomyces cerevisiae
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 344:6190, s. 1389-1392
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell species harbor ancestral structural homologs of caspase proteases, although the evolutionary benefit of such apoptosis-related proteins in unicellular organisms is unclear. Here, we found that the yeast metacaspase Mca1 is recruited to the insoluble protein deposit (IPOD) and juxtanuclear quality-control compartment (JUNQ) during aging and proteostatic stress. Elevating MCA1 expression counteracted accumulation of unfolded proteins and aggregates and extended life span in a heat shock protein Hsp104 disaggregase- and proteasome-dependent manner. Consistent with a role in protein quality control, genetic interaction analysis revealed that MCA1 buffers against deficiencies in the Hsp40 chaperone YDJ1 in a caspase cysteine-dependent manner. Life-span extension and aggregate management by Mca1 was only partly dependent on its conserved catalytic cysteine, which suggests that Mca1 harbors both caspase-dependent and independent functions related to life-span control.
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| 5. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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Restricted access: spatial sequestration of damaged proteins during stress and aging
- 2017
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Ingår i: Embo Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 18:3, s. 377-391
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Forskningsöversikt (refereegranskat)abstract
- The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging.
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| 6. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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Selective protein degradation ensures cellular longevity
- 2016
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Ingår i: eLife. - 2050-084X. ; 5:JUN2016
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Tidskriftsartikel (refereegranskat)abstract
- A previously unknown pathway can selectively degrade mitochondrial proteins in aged and stressed cells without destroying the organelle itself. © Vale and Hyman.
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| 7. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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The dual role of a yeast metacaspase: What doesn't kill you makes you stronger.
- 2015
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Ingår i: BioEssays : news and reviews in molecular, cellular and developmental biology. - : Wiley. - 1521-1878. ; 37:5, s. 525-531
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports suggest that the yeast Saccharomyces cerevisiae caspase-related metacaspase, Mca1, is required for cell-autonomous cytoprotective functions that slow cellular aging. Because the Mca1 protease has previously been suggested to be responsible for programmed cell death (PCD) upon stress and aging, these reports raise the question of how the opposing roles of Mca1 as a protector and executioner are regulated. One reconciling perspective could be that executioner activation may be restricted to situations where the death of part of the population would be beneficial, for example during colony growth or adaptation into specialized survival forms. Another possibility is that metacaspases primarily harbor beneficial functions and that the increased survival observed upon metacaspase removal is due to compensatory responses. Herein, we summarize data on the role of Mca1 in cell death and survival and approach the question of how a metacaspase involved in protein quality control may act as killer protein.
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| 8. |
- Hill, Sandra Malmgren, 1987, et al.
(författare)
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VCP/p97 regulates Beclin-1-dependent autophagy initiation
- 2021
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 17, s. 448-455
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Tidskriftsartikel (refereegranskat)abstract
- Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation.
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| 9. |
- Keuenhof, Katharina, 1994, et al.
(författare)
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Large organellar changes occur during mild heat shock in yeast
- 2021
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 135:5
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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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| 10. |
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