PfPPM2 signalling regulates asexual division and sexual conversion of human malaria parasite Plasmodium falciparum

Malaria parasite transits through distinct developmental stages during its life cycle in the human and mosquito host, which includes unique asynchronous division in the erythrocytes. The switch from its asexual stage to sexual forms, which is critical for disease transmission, is intricately regulated but signalling pathways involved in this process have remained unknown. In the present study, we report a novel signalling pathway involving Protein Phosphatase PfPPM2, which regulates asexual division of the parasite as well as its conversion to sexual forms. Phosphoproteomics revealed that PfPPM2 may regulate the phosphorylation of key proteins involved in chromatin remodelling and protein translation. One of the key PfPPM2-targets that emerged from these studies was Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing which contributes to both mitotic proliferation as well as sexual commitment of the parasite. We demonstrate that PfPPM2 promotes sexual conversion by regulating the interaction between HP1, H3K9me3 and chromatin and it achieves this by dephosphorylating S33 of HP1. Regulation of HP1 and Histone H3 by PfPPM2 may also contribute to division. In addition, PfPPM2 also regulates protein synthesis in the parasite by repressing the phosphorylation of initiation factor eIF2α, which is likely to contribute to parasite division and possibly sexual differentiation.