Plasmodium falciparum PP1 phosphatase is a key regulator of malaria parasite transmission

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ABSTRACT For the successful transmission of malaria parasites from humans to mosquitoes, Plasmodium falciparum gametocytes must remain in the bloodstream long enough to be taken up by a mosquito. Once ingested, they are then activated into gametes to continue the parasite life cycle in the mosquito midgut. Both persistence of gametocytes in the blood and their activation into gametes are tightly regulated by phospho-signaling. While the serine-threonine phosphatase Pf PP1 is an essential enzyme for parasite asexual proliferation, its role during transmission of sexual stages remains elusive. Here, we employed a conditional depletion strategy to conduct a functional analysis of Pf PP1 during gametocyte development, gamete activation and transmission to mosquitoes. We show that Pf PP1 regulates the deformability and the permeability of mature gametocyte-infected erythrocytes through the dephosphorylation of PKA substrates, thus highlighting a key role for Pf PP1 in modulating the host cell mechanical properties, which are crucial for gametocyte persistence in the bloodstream. We also provide evidence that Pf PP1 controls crucial steps of gamete activation via stimulation of the cGMP/ PKG pathway. Collectively, these results underscore the pivotal role of Pf PP1 in the transmission of P. falciparum to the mosquito during both sexual development and gamete activation. AUTHOR SUMMARY The protein phosphatase PP1 is a major contributor to total cellular phosphatase activity in eukaryotes and plays a critical role during various cellular processes. Here, we have unraveled novel mechanisms regulated by the phosphatase Pf PP1 in the human malaria parasite Plasmodium falciparum . While Pf PP1 is known to be essential for the parasite asexual proliferation, in the present study we demonstrate that Pf PP1 is also required during the sexual parasite stages, called gametocytes, that ensure parasite transmission from humans to mosquitoes. Pf PP1 is involved in regulating the mechanical properties of the gametocyte-infected host cell, a process necessary for the persistence of gametocytes in blood circulation. Moreover, Pf PP1 also contributes to the activation of gametocytes into gametes, the stages able to pursue the parasite life cycle in mosquitoes. In addition to providing insights into novel mechanisms involved in parasite transmission, this study also highlights the possibility of interfering with Pf PP1 signaling pathway for blocking malarial parasite transmission.

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