364-OR: Beta-Cell Glucose-Regulated Micropeptide 1 (BGRM1) Controls Cellular Homeostasis in Pancreatic Beta Cells

Abstract

Accumulating evidence demonstrates that certain types of long-noncoding RNAs (lncRNA) encode very short open reading frames, called micropeptides. By regulating larger protein complexes, these micropeptides can regulate fundamental biological processes such as skeletal muscle development and cell migration. However, the ability of micropeptides to maintain cellular and metabolic homeostasis in islets is unknown. Using a bioinformatics approach, we comprehensively analyzed the protein-coding potential of lncRNAs that are expressed in the human pancreas, and identified more than 30 that likely encode micropeptides. We further characterized one conserved IncRNA that encodes a 65-amino-acid micropeptide, which we named beta cell glucose regulated micropeptide 1 (BGRM1). We found that BGRM1 expression was altered in islets from obese or diabetic humans and mice. Overexpression of BGRM1 elevated glucose-stimulated insulin production in INS-1 cells and in islets from humans and mice. BGRM1 promotes endoplasmic reticulum (ER) calcium efflux and enhances cytosolic calcium levels, which suggests it mediates insulin production is in part by modulating intracellular calcium homeostasis. This notion is further supported by our mass spectra analysis that reveals several BGRM1 binding partners involved in ER calcium homeostasis in beta cells. Notably, BGRM1 is localized in the ER and protects beta cells from ER stress. Taken together, our study provides the first evidence that lncRNA encoded micropeptides play a critical role in pancreatic beta cell function. These results provide a foundation on which to perform future comprehensive analyses of micropeptide function and pathophysiological impact on diabetes. Disclosure M. Li: None. F. Shao: None. M.E. Sweat: None. Q. Qian: None. Y. Guo: None. S.B. Stephens: None. Y. Imai: None. L. Yang: None. H. Cao: None.