N6-adenosine methylation controls the translation of insulin mRNA

Abstract

Control of insulin mRNA translation is crucial for energy homeostasis, but the mechanisms remain largely unknown. We discovered that insulin mRNAs across invertebrates, vertebrates and mammals feature the modified base N⁶-methyladenosine (m⁶A). In flies, this RNA modification enhances insulin mRNA translation by promoting the association of the transcript with polysomes. Depleting m⁶A in Drosophila melanogaster insulin 2 mRNA (dilp2) directly through specific 3' untranslated region (UTR) mutations, or indirectly by mutating the m⁶A writer Mettl3, decreases dilp2 protein production, leading to aberrant energy homeostasis and diabetic-like phenotypes. Together, our findings reveal adenosine mRNA methylation as a key regulator of insulin protein synthesis with notable implications for energy balance and metabolic disease.