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

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 PfPP1 is an essential enzyme for asexual blood stage parasite proliferation, its role during transmission of sexual stages remains elusive. Here, we employed a conditional depletion strategy to conduct a functional analysis of PfPP1 during gametocyte development, gamete formation, and transmission to mosquitoes. We show that PfPP1 regulates the deformability and the permeability of mature gametocyte-infected erythrocytes through the dephosphorylation of protein kinase A (PKA) substrates, thus highlighting a key role for PfPP1 in modulating the host cell mechanical properties, which are crucial for gametocyte persistence in the bloodstream. We also provide evidence that PfPP1 controls crucial steps of gametocyte activation via stimulation of the cyclic GMP (cGMP)/protein kinase G (PKG) pathway. Collectively, these results underscore the pivotal role of PfPP1 in the transmission of P. falciparum to the mosquito during both gametocyte development and gamete formation.IMPORTANCE 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 PfPP1 in the human malaria parasite Plasmodium falciparum. While PfPP1 is known to be essential for the parasite’s asexual proliferation, in the present study, we demonstrate that PfPP1 is also required during the sexual parasite stages, called gametocytes, that ensure parasite transmission from humans to mosquitoes. PfPP1 regulates the mechanical properties of the gametocyte-infected host cell, a process necessary for gametocyte persistence in blood circulation. Moreover, PfPP1 also contributes to the activation of gametocytes into gametes, the stages that 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 the PfPP1 signaling pathway for blocking malarial parasite transmission.