Protein phosphatase PfPPM2 signaling and dephosphorylation of  Heterochromatin HP1 is critical for  asexual division and sexual differentiation of malaria parasite.
We demonstrate that Protein Phosphatase PfPPM2 regulates both asexual and sexual development of human malaria parasite P. falciparum.  It is involved in  the division of the parasite during asexual development and promotes its sexual differentiation. Phosphoproteomics studies revealed that PfPPM2 targets in the parasite include key regulators of protein translation and chromatin remodelling. We demonstrate that it regulates dephosphorylation of S33 of Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing and contributes to both mitotic proliferation as well as sexual differentiation of the parasite into sexual forms. Detailed investigations revealed that PfPPM2 mediated dephosphorylation of HP1 at S33 is a signal for parasite sexual conversion. HP1- S33 dephosphorylation impairs its interaction with trimethylated form of histone 3 (H3) at lysine 9 (H3K9me3), which is known to stabilize the heterochromatin. As a result, the expression of transcription of ap2g-which is repressed by HP1-H3K9me3-was stimulated resulting in sexual conversion of the parasite. Interestingly, the state of HP1-S33 phosphorylation seems to largely reflect the fate of the parasite-its optimal phosphorylation is important for asexual division whereas it is dephosphorylated form favours sexual differentiation. PfPPM2 also regulates protein synthesis in the parasite by repressing a signaling pathway involved in the phosphorylation of initiation factor eIF2a, which are likely to contribute to parasite division and possibly differentiation. Overall design: PfPPM2-HA-glmS:Nf54 parasites were either left untreated or treated with GlcN (cycle 0, rings)  and parasite pellets were prepared (schizonts, cycle 1) and  RNAseq analysis was perform  to compare global changes in transcriptome of these parasites upon PfPPM2 depletion.