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Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.

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Author

  • Benjamin D Moore
  • Ramon U Jin
  • Heiyong Lo
  • Min Jung
  • Haiyan Wang
  • Michele A Battle
  • Claes Wollheim
  • Fumihiko Urano
  • Jason C Mills

Summary, in English

The transcription factor, X-box Binding Protein-One (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4-alpha (HNF4α) directly induces XBP1 expression. Mutations in HNF4α cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human-disease-allele point mutants or knockout and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca2+ signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca2+ homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4α-deficient β-cells. Our findings uncover a transcriptional relationship between HNF4α and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.

Publishing year

2016-01-20

Language

English

Pages

6146-6157

Publication/Series

Journal of Biological Chemistry

Volume

291

Issue

12

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Translational Muscle Research

ISBN/ISSN/Other

  • ISSN: 1083-351X