Abstract
BackgroundGene expression is controlled at multiple levels, including transcription, stability, translation, and degradation. Over the years, it has become apparent that Plasmodium falciparum exerts limited transcriptional control of gene expression, while at least part of Plasmodium’s genome is controlled by post-transcriptional mechanisms. To generate insights into the mechanisms that regulate gene expression at the post-transcriptional level, we undertook complementary computational, comparative genomics, and experimental approaches to identify and characterize mRNA-binding proteins (mRBPs) in P. falciparum.ResultsClose to 1000 RNA-binding proteins are identified by hidden Markov model searches, of which mRBPs encompass a relatively large proportion of the parasite proteome as compared to other eukaryotes. Several abundant mRNA-binding domains are enriched in apicomplexan parasites, while strong depletion of mRNA-binding domains involved in RNA degradation is observed. Next, we experimentally capture 199 proteins that interact with mRNA during the blood stages, 64 of which with high confidence. These captured mRBPs show a significant overlap with the in silico identified candidate RBPs (p < 0.0001). Among the experimentally validated mRBPs are many known translational regulators active in other stages of the parasite’s life cycle, such as DOZI, CITH, PfCELF2, Musashi, and PfAlba1–4. Finally, we also detect several proteins with an RNA-binding domain abundant in Apicomplexans (RAP domain) that is almost exclusively found in apicomplexan parasites.ConclusionsCollectively, our results provide the most complete comparative genomics and experimental analysis of mRBPs in P. falciparum. A better understanding of these regulatory proteins will not only give insight into the intricate parasite life cycle but may also provide targets for novel therapeutic strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1014-0) contains supplementary material, which is available to authorized users.
Highlights
Gene expression is controlled at multiple levels, including transcription, stability, translation, and degradation
Collectively, our results provide the most complete comparative genomics and experimental analysis of mRNA-binding proteins (mRBPs) in P. falciparum
Identification and classification of RNA-binding proteins in P. falciparum To characterize the repertoire of RNA-binding proteins (RBPs) in P. falciparum, we performed a hidden Markov model (HMM) search on the parasite proteome using 793 domains from the protein family (Pfam) database that are known to interact with RNA or that are found in RNA-related proteins (Additional file 1)
Summary
Gene expression is controlled at multiple levels, including transcription, stability, translation, and degradation. It has become apparent that Plasmodium falciparum exerts limited transcriptional control of gene expression, while at least part of Plasmodium’s genome is controlled by post-transcriptional mechanisms. To generate insights into the mechanisms that regulate gene expression at the post-transcriptional level, we undertook complementary computational, comparative genomics, and experimental approaches to identify and characterize mRNA-binding proteins (mRBPs) in P. falciparum. Despite continued efforts aimed at preventing infections, treatment of infected individuals is still an essential part of the strategy to reduce malaria morbidity and mortality. Gene expression is controlled at multiple levels by means of mechanisms that regulate gene transcription or that act post-transcriptionally to affect the stability or translational efficiency of the transcript. It has become apparent that P. falciparum exerts limited
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