GID/CTLH E3 ligase complex control cell fate programs for sexual development of Plasmodium falciparum

Transmission of the malaria parasite Plasmodium falciparum requires the formation of specialised sexual cells called gametocytes. A hallmark of P. falciparum gametocyte development is its long duration, during which the parasite undergoes dramatic cellular remodelling including morphological, physiological and metabolic changes which result in the formation of a transmission ready, stage V gametocyte. Here we show that the PfGID E3 ubiquitin ligase complex regulates critical gametocyte cell fate programmes through the targeted ubiquitination of key proteins. Deletion of PfGID complex components leads to an arrest in gametocyte development and a loss of transmission to mosquitoes. PfGID governs gametocyte development by fine-tuning the protein levels of two substrates: the ZFP36 family RNAbinding protein GD1, and PfDPL, a cryptochrome-like protein. Our findings reveal that PfDPL regulates the expression of male-specific proteins early in gametocyte development that are essential for gametogenesis. In parallel to the PfDPL controlled cell fate program the RNA binding protein GD1 regulates transcripts crucial for gametocyte development by holding them in a state of translational repression. These findings illuminate the intricate molecular choreography underlying Plasmodium sexual development and provide insights into how single-celled eukaryotes execute cell-fate programmes to navigate complex life cycles and adapt to diverse host environments.