CDPK4 is a pleiotropic regulator controlling the atypical Plasmodium cell cycle during mosquito transmission

ABSTRACT: Transmission of malaria parasites from humans to the mosquito vector exclusively relies on the sexual reproduction of the parasite within the mosquito blood meal. Upon ingestion, Plasmodium male gametocyte undergoes explosive development: within 10 minutes, it completes three rounds of genome replication and endomitosis, assembles eight axonemes, and emerges from the host red blood cell. The plant-like calcium-dependent protein kinase 4 (CDPK4) was previously shown to be essential for male gametogenesis placing this kinase as an attractive drug target to block malaria transmission. Here we have identified and resolved three distinct molecular functions of CDPK4 during male gametogenesis. Activity of a myristoylated isoform is first required up to 20 seconds after activation to load the Mini-Chromosome Maintenance complex onto origins of replication. This role is partially mediated by a conserved protein belonging to the SAPS-domain family which is involved in the G1 to S-phase transition in eukaryotes. At the same time, activity of myristoylated CDPK4 is required to phosphorylate a Plasmodium-specific microtubule-associated protein necessary for mitotic spindle assembly. Finally, activity of a short non-myristoylated isoform of CDPK4 is essential seconds prior to completion of cytokinesis and the activation of male gamete motility. This late role has been linked to another Plasmodium-specific protein that is incorporated into axonemes during gametogenesis. This study reveals how a kinase of a protist parasite integrates and transduces multiple signals with a high spatiotemporal resolution to control both evolutionarily conserved and Plasmodium-specific biological processes.

INSTRUMENT(S): LTQ Orbitrap Velos, Orbitrap Fusion

ORGANISM(S): Plasmodium Berghei Mus Musculus (mouse)

SUBMITTER: James Wright  

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD005884 | Pride | 2017-05-24

REPOSITORIES: Pride