Anks4b, a novel target of HNF4α protein, interacts with GRP78 protein and regulates endoplasmic reticulum stress-induced apoptosis in pancreatic β-cells.

Sato Y, Hatta M, Karim MF, Sawa T, Wei FY, Sato S, Magnuson MA, Gonzalez FJ, Tomizawa K, Akaike T, Yoshizawa T, Yamagata K
J Biol Chem. 2012 287 (27): 23236-45

PMID: 22589549 · PMCID: PMC3391104 · DOI:10.1074/jbc.M112.368779

Mutations of the HNF4A gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of pancreatic β-cell function. HNF4α is a transcription factor belonging to the nuclear receptor superfamily (NR2A1), but its target genes in pancreatic β-cells are largely unknown. Here, we report that ankyrin repeat and sterile α motif domain containing 4b (Anks4b) is a target of HNF4α in pancreatic β-cells. Expression of Anks4b was decreased in both βHNF4α KO islets and HNF4α knockdown MIN6 β-cells, and HNF4α 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 β-cell susceptibility to ER stress-induced apoptosis. These results indicate that Anks4b is a HNF4α target gene that regulates ER stress in β-cells by interacting with GRP78, thus suggesting that HNF4α is involved in maintenance of the ER.

MeSH Terms (17)

Animals Apoptosis Carrier Proteins Cell Line, Tumor Diabetes Mellitus, Type 2 Endoplasmic Reticulum Endoplasmic Reticulum Stress Female Gene Expression Profiling Heat-Shock Proteins Insulin-Secreting Cells Insulinoma Mice Mice, Knockout Pancreatic Neoplasms Proteomics Transcriptional Activation

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