| 1. |
- Chan, Sherwin, et al.
(author)
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Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor
- 2017
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In: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 2:7
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Journal article (peer-reviewed)abstract
- Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
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| 2. |
- Goel, Suchi, et al.
(author)
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RIFINs are adhesins implicated in severe Plasmodium falciparum malaria
- 2015
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 21:4, s. 314-317
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Journal article (peer-reviewed)abstract
- Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), bind to RBCs-preferentially of blood group A-to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.
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| 3. |
- Joannin, Nicolas
(author)
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Antigenic variation in Plasmodium falciparum : understanding the RIFIN protein family
- 2010
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Doctoral thesis (other academic/artistic)abstract
- RIFIN proteins are variable surface antigens, which have a central role in the survival and virulence of the malaria parasite Plasmodium falciparum. Antigenic variation is a mean for these parasites to avoid clearance by the host s immune system. However, this is often a secondary function to the main role of these proteins. In the case of RIFIN, P. falciparum s largest multicopy protein family, the main functions remain unknown. In order to elucidate a protein s function, it is crucial to understand its basic properties, including the structure of the protein family, their localization and the protein s topology. Through different methods, we have strived to simplify the RIFIN protein family into manageable entities. We have started with a simple classification of RIFIN proteins into meaningful sub-groups. We have predicted that these sub-groups are functionally distinct, although they probably share a related function. We then designed RSPred, an automatic method, based on hidden Markov models and a sorting program, to detect and classify RIFIN and STEVOR sequences according to their sub-group. Finally, using an in vitro method to determine protein topology, we have analyzed both A-RIFIN and B-RIFIN proteins for their number of transmembrane segments and their topologies. We show that both protein groups have a signal sequence targeting them to lipid bilayers and only one transmembrane domain. They both share a common topology where the bulk of the protein is exposed to the extracellular environment. With the current knowledge of RIFIN protein localizations, as well as the loss of expression of A-RIFIN but not B-RIFIN proteins in a splenectomized patient, it seems increasingly clear that B-RIFIN proteins are good targets for future studies, to decipher the functions of these variable proteins.
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| 4. |
- Joannin, Nicolas, et al.
(author)
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RSpred, a set of Hidden Markov Models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum
- 2011
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In: BMC Genomics. - : BioMed Central. - 1471-2164. ; 12:119
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Journal article (peer-reviewed)abstract
- Background: Many parasites use multicopy protein families to avoid their hosts immune system through a strategy called antigenic variation. RIFIN and STEVOR proteins are variable surface antigens uniquely found in the malaria parasites Plasmodium falciparum and P. reichenowi. Although these two protein families are different, they have more similarity to each other than to any other proteins described to date. As a result, they have been grouped together in one Pfam domain. However, a recent study has described the sub-division of the RIFIN protein family into several functionally distinct groups. These sub-groups require phylogenetic analysis to sort out, which is not practical for large-scale projects, such as the sequencing of patient isolates and meta-genomic analysis. Results: We have manually curated the rif and stevor gene repertoires of two Plasmodium falciparum genomes, isolates DD2 and HB3. We have identified 25% of mis-annotated and similar to 30 missing rif and stevor genes. Using these data sets, as well as sequences from the well curated reference genome (isolate 3D7) and field isolate data from Uniprot, we have developed a tool named RSpred. The tool, based on a set of hidden Markov models and an evaluation program, automatically identifies STEVOR and RIFIN sequences as well as the sub-groups: A-RIFIN, B-RIFIN, B1-RIFIN and B2-RIFIN. In addition to these groups, we distinguish a small subset of STEVOR proteins that we named STEVOR-like, as they either differ remarkably from typical STEVOR proteins or are too fragmented to reach a high enough score. When compared to Pfam and TIGRFAMs, RSpred proves to be a more robust and more sensitive method. We have applied RSpred to the proteomes of several P. falciparum strains, P. reichenowi, P. vivax, P. knowlesi and the rodent malaria species. All groups were found in the P. falciparum strains, and also in the P. reichenowi parasite, whereas none were predicted in the other species. Conclusions: We have generated a tool for the sorting of RIFIN and STEVOR proteins, large antigenic variant protein groups, into homogeneous sub-families. Assigning functions to such protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. RSpred removes the need for complicated and time consuming phylogenetic analysis methods. It will benefit both research groups sequencing whole genomes as well as others working with field isolates. RSpred is freely accessible via http://www.ifm.liu.se/bioinfo/.
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| 5. |
- Joannin, Nicolas, et al.
(author)
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Sub-grouping and sub-functionalization of the RIFIN multi-copy protein family.
- 2008
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 9, s. 19-
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Journal article (peer-reviewed)abstract
- BACKGROUND: Parasitic protozoans possess many multicopy gene families which have central roles in parasite survival and virulence. The number and variability of members of these gene families often make it difficult to predict possible functions of the encoded proteins. The families of extra-cellular proteins that are exposed to a host immune response have been driven via immune selection to become antigenically variant, and thereby avoid immune recognition while maintaining protein function to establish a chronic infection. RESULTS: We have combined phylogenetic and function shift analyses to study the evolution of the RIFIN proteins, which are antigenically variant and are encoded by the largest multicopy gene family in Plasmodium falciparum. We show that this family can be subdivided into two major groups that we named A- and B-RIFIN proteins. This suggested sub-grouping is supported by a recently published study that showed that, despite the presence of the Plasmodium export (PEXEL) motif in all RIFIN variants, proteins from each group have different cellular localizations during the intraerythrocytic life cycle of the parasite. In the present study we show that function shift analysis, a novel technique to predict functional divergence between sub-groups of a protein family, indicates that RIFINs have undergone neo- or sub-functionalization. CONCLUSION: These results question the general trend of clustering large antigenically variant protein groups into homogenous families. Assigning functions to protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. Using phylogenetic and function shift analysis methods, we identify new directions for the investigation of this broad and complex group of proteins.
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