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Insulator-like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum.

ABSTRACT: Plasmodium falciparum causes the deadliest form of human malaria. Its virulence is attributed to its ability to modify the infected RBC and to evade human immune attack through antigenic variation. Antigenic variation is achieved through tight regulation of antigenic switches between variable surface antigens named "P. falciparum erythrocyte membrane protein-1" encoded by the var multicopy gene family. Individual parasites express only a single var gene at a time, maintaining the remaining var genes in a transcriptionally silent state. Strict pairing between var gene promoters and a second promoter within an intron found in each var gene is required for silencing and counting of var genes by the mechanism that controls mutually exclusive expression. We have identified and characterized insulator-like DNA elements that are required for pairing var promoters and introns and thus are essential for regulating silencing and mutually exclusive expression. These elements, found in the regulatory regions of each var gene, are bound by distinct nuclear protein complexes. Any alteration in the specific, paired structure of these elements by either deletion or insertion of additional elements results in an unregulated var gene. We propose a model by which silencing and mutually exclusive expression of var genes is regulated by the precise arrangement of insulator-like DNA pairing elements.

SUBMITTER: Avraham I

PROVIDER: S-EPMC3535642 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Insulator-like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum.

Avraham Inbar I Schreier Jeremy J Dzikowski Ron R

Proceedings of the National Academy of Sciences of the United States of America 20121129 52

Plasmodium falciparum causes the deadliest form of human malaria. Its virulence is attributed to its ability to modify the infected RBC and to evade human immune attack through antigenic variation. Antigenic variation is achieved through tight regulation of antigenic switches between variable surface antigens named "P. falciparum erythrocyte membrane protein-1" encoded by the var multicopy gene family. Individual parasites express only a single var gene at a time, maintaining the remaining var g ...[more]

PMID: 23197831

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Project description:BackgroundMalaria continues to be one of the most severe global infectious diseases, responsible for 1-2 million deaths yearly. The rapid evolution and spread of drug resistance in parasites has led to an urgent need for the development of novel antimalarial targets. Proteases are a group of enzymes that play essential roles in parasite growth and invasion. The possibility of designing specific inhibitors for proteases makes them promising drug targets. Previously, combining a comparative genomics approach and a machine learning approach, we identified the complement of proteases (degradome) in the malaria parasite Plasmodium falciparum and its sibling species 123, providing a catalog of targets for functional characterization and rational inhibitor design. Network analysis represents another route to revealing the role of proteins in the biology of parasites and we use this approach here to expand our understanding of the systems involving the proteases of P. falciparum.ResultsWe investigated the roles of proteases in the parasite life cycle by constructing a network using protein-protein association data from the STRING database 4, and analyzing these data, in conjunction with the data from protein-protein interaction assays using the yeast 2-hybrid (Y2H) system 5, blood stage microarray experiments 678, proteomics 9101112, literature text mining, and sequence homology analysis. Seventy-seven (77) out of 124 predicted proteases were associated with at least one other protein, constituting 2,431 protein-protein interactions (PPIs). These proteases appear to play diverse roles in metabolism, cell cycle regulation, invasion and infection. Their degrees of connectivity (i.e., connections to other proteins), range from one to 143. The largest protease-associated sub-network is the ubiquitin-proteasome system which is crucial for protein recycling and stress response. Proteases are also implicated in heat shock response, signal peptide processing, cell cycle progression, transcriptional regulation, and signal transduction networks.ConclusionsOur network analysis of proteases from P. falciparum uses a so-called guilt-by-association approach to extract sets of proteins from the proteome that are candidates for further study. Novel protease targets and previously unrecognized members of the protease-associated sub-systems provide new insights into the mechanisms underlying parasitism, pathogenesis and virulence.

Dataset Information

Insulator-like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum.

Publications

Insulator-like pairing elements regulate silencing and mutually exclusive expression in the malaria parasite Plasmodium falciparum.

Similar Datasets

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