A Putative Long noncoding RNA‐encoded Micropeptide Maintains Cellular Homeostasis in Pancreatic β‐cells

Abstract

Introduction Micropeptides encoded by transcripts previously annotated as long noncoding RNA (IncRNAs) are emerging as important mediators of fundamental biological processes such as muscle performance, mTORC1 activation and cell movement. Here we experimentally verified one such micropeptide encoded by a β-cell- and neural cell-enriched lncRNA TUNAR. We named this highly conserved 48-amino-acid micropeptide Beta cell- and Neural cell-regulin (BNLN). Materials and Methods BNLN constructs were transfected into 293T and INS-1 cells to determine BNLN expression pattern and function. Ca2+([Ca2+]ER and [Ca2+]c) level and glucose-stimulated insulin secretion (GSIS) were assessed in INS-1 cells with BNLN overexpression or mice islets to understand BNLN function to pancreatic β-cells. Results BNLN contains a single-pass transmembrane domain and localized at the endoplasmic reticulum (ER) in pancreatic β-cells. Overexpression of BNLN lowered ER calcium levels, maintained ER homeostasis, and elevated glucose-stimulated insulin secretion in pancreatic β-cells. We further assessed the BNLN expression in islets from mice fed with a high-fat diet and a regular diet, and found that BNLN is suppressed by diet-induced obesity (DIO). Conversely, overexpression of BNLN enhanced insulin secretion in islets from lean and obese mice as well as from humans. Conclusion Our study provides the first evidence that lncRNA-encoded micropeptides play a critical role in pancreatic β-cell function and provides a foundation for future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes.