Histone H2B monoubiquitination drives sexual commitment in malaria parasites.

Transmission of malaria parasites to mosquito vectors relies on the successful conversion from asexual blood-stage forms into sexual gametocytes. Protein ubiquitination regulates many cellular processes, including cell differentiation in other eukaryotes, but whether specific ubiquitination machinery mediates Plasmodium sexual conversion is unclear. Here we conduct CRISPR-Cas9 mutagenesis screens to systematically profile Plasmodium yoelii E2 ubiquitin-conjugating enzymes for their impact on parasite development. We demonstrate that an E2 enzyme (Rad6B), and its partner RING-type E3 ligase (Tex1), play determinant roles in gametocytogenesis and transmission to mosquitoes. Deletion of either Rad6B or Tex1 results in severe defects in gametocyte production and oocyst formation. The Rad6B-Tex1 complex catalyses histone H2B monoubiquitination in Plasmodium yoelii and Plasmodium falciparum. H2B monoubiquitination promotes H3K4 tri-methylation occupancy at the promoter region of the gene encoding transcription factor AP2-G, a master regulator of sexual conversion, thereby inducing ap2-g expression and initiating sexual commitment. These findings reveal a key epigenetic mechanism leading to sexual differentiation in both human and rodent malaria parasites, providing potential targets for transmission-blocking interventions.