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

ABSTRACTFor the successful transmission of malaria parasites from humans to mosquitoes,Plasmodium falciparumgametocytes 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 phosphatasePfPP1 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 ofPfPP1 during gametocyte development, gamete activation and transmission to mosquitoes. We show thatPfPP1 regulates the deformability and the permeability of mature gametocyte-infected erythrocytes through the dephosphorylation of PKA substrates, thus highlighting a key role forPfPP1 in modulating the host cell mechanical properties, which are crucial for gametocyte persistence in the bloodstream. We also provide evidence thatPfPP1 controls crucial steps of gamete activation via stimulation of the cGMP/ PKG pathway. Collectively, these results underscore the pivotal role ofPfPP1 in the transmission ofP. falciparumto the mosquito during both sexual development and gamete activation.AUTHOR SUMMARYThe 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 phosphatasePfPP1 in the human malaria parasitePlasmodium falciparum. WhilePfPP1 is known to be essential for the parasite asexual proliferation, in the present study we demonstrate thatPfPP1 is also required during the sexual parasite stages, called gametocytes, that ensure parasite transmission from humans to mosquitoes.PfPP1 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,PfPP1 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 withPfPP1 signaling pathway for blocking malarial parasite transmission.