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

Yoshifumi Sato, Mitsutoki Hatta, Md Fazlul Karim, Tomohiro Sawa, Fan Yan Wei, Shoki Sato, Mark A. Magnuson, Frank J. Gonzalez, Kazuhito Tomizawa, Takaaki Akaike, Tatsuya Yoshizawa, Kazuya Yamagata

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)23236-23245
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number27
DOIs
Publication statusPublished - Jun 29 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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