Small RNAs derived from tRNA fragmentation regulate the functional maturation of neonatal β cells

作者：Mustafa Bilal Bayazit, Cécile Jacovetti, Cristina Cosentino, Jonathan Sobel, Kejing Wu, Flora Brozzi, Adriana Rodriguez‐Trejo, Lisa Stoll, Claudiane Guay, Romano Regazzi · 发表于：Cell Reports · 年份：2022 · DOI：10.1016/j.celrep.2022.111069 · 被引用次数：28 · 研究领域：Pancreatic function and diabetes、RNA modifications and cancer、Genetics and Neurodevelopmental Disorders

tRNA-derived fragments (tRFs) are an emerging class of small non-coding RNAs with distinct cellular functions. Here, we studied the contribution of tRFs to the regulation of postnatal β cell maturation, a critical process that may lead to diabetes susceptibility in adulthood. We identified three tRFs abundant in neonatal rat islets originating from 5′ halves (tiRNA-5s) of histidine and glutamate tRNAs. Their inhibition in these islets reduced β cell proliferation and insulin secretion. Mitochondrial respiration was also perturbed, fitting with the mitochondrial enrichment of nuclear-encoded tiRNA-5 HisGTG and tiRNA-5 GluCTC . Notably, tiRNA-5 inhibition reduced Mpc1, a mitochondrial pyruvate carrier whose knock down largely phenocopied tiRNA-5 inhibition. tiRNA-5 HisGTG interactome revealed binding to Musashi-1, which was essential for the mitochondrial enrichment of tiRNA-5 HisGTG . Finally, tiRNA-5s were dysregulated in the islets of diabetic and diabetes-prone animals. Altogether, tiRNA-5s represent a class of regulators of β cell maturation, and their deregulation in neonatal islets may lead to diabetes susceptibility in adulthood.