N⁶-methyladenosine primes the malaria parasite for transmission

Abstract

Posted March 28, 2025 on bioRxiv.International audienceSudden environmental changes are a recurring challenge for unicellular organisms, but a necessity for many to progress through their lifecycle. To transmit from its human host to mosquito vector, malaria parasites differentiate into male and female, semi-quiescent stages that can re-initiate development within seconds after transmission. Here, we identify the RNA modification N 6 methyladenosine (m 6 A) as the mediator of a rapid, sex-specific, and temperature-sensitive mechanism to restructure protein synthesis during transmission. We find that male parasites maintain high levels of translation during their semi-quiescence that are rapidly repressed following mosquito uptake. This translational shutdown is essential for the continuation of male parasite development and depends on the m 6 A-binding protein YTH.2. We further show that m 6 A and YTH.2 are already present prior to transmission, but that their repressive interaction requires a temperature drop accompanying the exit from the human host. Hence, m 6 A appears to prime the parasite transcriptome and subsequently converts an environmental shift into a rapid translational response.</div