m5C tRNA methylation in Plasmodium falciparum

Malaria parasites have evolved a well-adjusted developmental program to progress through the complex life cycle in the human and mosquito host. Here we identify cytosine methylation of tRNAAsp (GTC) as being critical to maintain stable protein synthesis. Using conditional knock out of a member of the DNA methyltransferases family called Pf-DNMT2, RNA bisulfite sequencing demonstrates the selective cytosine methylation of this enzyme of tRNAAsp (GTC) at position C38. Although no growth defect on parasite proliferation was observed, Pf-DNMT2 KO parasites show a selective downregulation of proteins with a GAC codon bias. This results in a significant shift in parasite metabolism, priming KO parasites for being more sensitive to various types of stress. Importantly, nutritional stress makes tRNAAsp (GTC) sensitive to cleavage by an unknown nuclease and increases gametocyte production (>6-fold). Here we identify an epitranscriptomic mechanism that safeguards protein translation and homeostasis of sexual commitment in malaria parasites.