Abstract
Malaria parasites require multiple phosphorylation and dephosphorylation steps to drive signaling pathways for proper differentiation and transformation. Several protein phosphatases, including protein phosphatase 1 (PP1), one of the main dephosphorylation enzymes, have been shown to be indispensable for the Plasmodium life cycle. The catalytic subunit of PP1 (PP1c) participates in cellular processes via dynamic interactions with a vast number of binding partners that contribute to its diversity of action. In this study, we used Plasmodium berghei transgenic parasite strains stably expressing PP1c or its inhibitor 2 (I2) tagged with mCherry, combined with the mCherry affinity pulldown of proteins from asexual and sexual stages, followed by mass spectrometry analyses. Mapped proteins were used to identify interactomes and to cluster functionally related proteins. Our findings confirm previously known physical interactions of PP1c and reveal enrichment of common biological processes linked to cellular component assembly in both schizonts and gametocytes to biosynthetic processes/translation in schizonts and to protein transport exclusively in gametocytes. Further, our analysis of PP1c and I2 interactomes revealed that nuclear export mediator factor and peptidyl-prolyl cis-trans isomerase, suggested to be essential in P. falciparum, could be potential targets of the complex PP1c/I2 in both asexual and sexual stages. Our study emphasizes the adaptability of Plasmodium PP1 and provides a fundamental study of the protein interaction landscapes involved in a myriad of events in Plasmodium, suggesting why it is crucial to the parasite and a source for alternative therapeutic strategies.
Highlights
Malaria is a parasitic disease of major public health importance caused mainly by Plasmodium falciparum
Here, the interactomes of PbPP1c and PbI2, showing common and specific interactors depending on the Plasmodium parasite stage
As for PbI2, a parasite line expressing mCherry-tagged inhibitor 2 (I2) from its endogenous locus was generated in the same strain used for PbPP1c
Summary
Malaria is a parasitic disease of major public health importance caused mainly by Plasmodium falciparum. The search for new targets and drugs is imperative In this context, one strategy is to decipher orthologues of proteins described to play essential roles in other eukaryotes in order to target them in the malaria parasite. One strategy is to decipher orthologues of proteins described to play essential roles in other eukaryotes in order to target them in the malaria parasite Among these proteins, due to the fact of their pleiotropic roles in the dynamic regulation of protein function and cellular distribution, enzymes involved in dephosphorylation processes and, in particular protein phosphatase 1 (PP1), are of interest. The PP1 catalytic subunit itself could be considered a promising target for the development of innovative and effective drugs against malaria This could be difficult to achieve, as PP1c is highly conserved in eukaryotes
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