Plasmodium falciparum Guanylyl Cyclase-Alpha and the Activity of Its Appended P4-ATPase Domain Are Essential for cGMP Synthesis and Blood-Stage Egress.

摘要: Guanylyl cyclases (GCs) synthesize cyclic GMP (cGMP) and, together with nucleotide phosphodiesterases, are responsible for regulating levels of this intracellular messenger which mediates myriad functions across eukaryotes. In malaria parasites (Plasmodium spp), as well their apicomplexan and ciliate relatives, GCs associated a P4-ATPase-like domain in unique bifunctional configuration. P4-ATPases generate membrane bilayer lipid asymmetry by translocating phospholipids from the outer to inner leaflet. Here, we investigate role Plasmodium falciparum guanylyl cyclase alpha (GCα) its P4-ATPase module, showing that asexual blood-stage lacking both domains unable egress host erythrocytes. GCα-null cannot cGMP or mobilize calcium, cGMP-dependent protein kinase (PKG)-driven requirement egress. Using chemical complementation analogue point mutagenesis crucial conserved residue within domain, show activity is upstream linked synthesis. Collectively, our results demonstrate GCα critical regulator PKG plays primary generating merozoite egress.IMPORTANCE The clinical manifestations arise due successive rounds replication red blood cells. Once mature, daughter merozoites released infected erythrocytes invade new cells tightly regulated process termed Previous studies have shown activation signaling initiating GCα, enzyme, sole enzyme production during stages required cellular events leading up We further addition GC appended ATPase-like also involved production. Our highlight orchestrating parasite