Anks4b, a Novel Target of HNF4α Protein, Interacts with GRP78 Protein and Regulates Endoplasmic Reticulum Stress-induced Apoptosis in Pancreatic β-Cells

Mutations of the HNF4A gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of pancreatic beta-cell function. HNF4 alpha is a transcription factor belonging to the nuclear receptor superfamily (NR2A1), but its target genes in pancreatic beta-cells are largely unknown. Here, we report that ankyrin repeat and sterile alpha motif domain containing 4b (Anks4b) is a target of HNF4 alpha in pancreatic beta-cells. Expression of Anks4b was decreased in both beta HNF4 alpha KO islets and HNF4 alpha knockdown MIN6 beta-cells, and HNF4 alpha activated Anks4b promoter activity. Anks4b bound to glucose-regulated protein 78 (GRP78), a major endoplasmic reticulum (ER) chaperone protein, and overexpression of Anks4b enhanced the ER stress response and ER stress-associated apoptosis of MIN6 cells. Conversely, suppression of Anks4b reduced beta-cell susceptibility to ER stress-induced apoptosis. These results indicate that Anks4b is a HNF4 alpha target gene that regulates ER stress in beta-cells by interacting with GRP78, thus suggesting that HNF4 alpha is involved in maintenance of the ER.