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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. J Biol Chem 2016 Mar 18;291(12):6146-57

Date

01/23/2016

Pubmed ID

26792861

Pubmed Central ID

PMC4813565

DOI

10.1074/jbc.M115.685750

Scopus ID

2-s2.0-84964891117   18 Citations

Abstract

The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4α (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 knock-out and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca(2+) 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.

Author List

Moore BD, Jin RU, Lo H, Jung M, Wang H, Battle MA, Wollheim CB, Urano F, Mills JC

Author

Michele A. Battle PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Calcium
Cell Line
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Endoplasmic Reticulum
Gene Expression Regulation
Glucose
HEK293 Cells
Hepatocyte Nuclear Factor 4
Homeostasis
Humans
Insulin
Insulin-Secreting Cells
Mice
Regulatory Factor X Transcription Factors
Transcription Factors
Transcription, Genetic
X-Box Binding Protein 1