N6-Adenosine methylation regulates the translation of insulin mRNA

Abstract

Relatively little is known about the first step of insulin synthesis: the translation of the mRNA. Here we show that the translation of D. melanogaster insulin 2 mRNA (dilp2) is controlled by methylation of N6-adenosine (m6A) in the 3 UTR. Mutations in the m6A writer Mettl3 and methylated-residues in the dilp2 3UTR decreased the levels of dilp2 mRNA associated with the polysomes, and the total amount of dilp2 protein produced. This resulted in aberrant energy homeostasis and diabetic-like phenotypes, consistent with the specific function of dilp2 in adult metabolism. Conserved m6A signatures were also identified in the 3 UTRs of vertebrate insulin mRNAs. These data identify m6A as a key regulator of insulin protein synthesis and energy homeostasis in metazoans and demonstrate an essential role for m6A in translation, with important implications for diabetes and metabolic disease. One-Sentence SummaryThe most abundant modification in eukaryotic mRNAs controls the synthesis of insulin protein in D. melanogaster.