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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.

Moore, Benjamin D; Jin, Ramon U; Lo, Heiyong; Jung, Min; Wang, Haiyan; Battle, Michele A; Wollheim, Claes LU ; Urano, Fumihiko and Mills, Jason C (2016) In Journal of Biological Chemistry 291(12). p.6146-6157
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
291
issue
12
pages
6146 - 6157
publisher
ASBMB
external identifiers
  • pmid:26792861
  • wos:000372894200009
  • scopus:84964891117
ISSN
1083-351X
DOI
10.1074/jbc.M115.685750
language
English
LU publication?
yes
id
cfc600a9-9048-4c96-8416-95e0d06628a3 (old id 8576690)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26792861?dopt=Abstract
date added to LUP
2016-02-03 21:32:14
date last changed
2017-05-21 04:32:09
@article{cfc600a9-9048-4c96-8416-95e0d06628a3,
  abstract     = {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.},
  author       = {Moore, Benjamin D and Jin, Ramon U and Lo, Heiyong and Jung, Min and Wang, Haiyan and Battle, Michele A and Wollheim, Claes and Urano, Fumihiko and Mills, Jason C},
  issn         = {1083-351X},
  language     = {eng},
  month        = {01},
  number       = {12},
  pages        = {6146--6157},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.},
  url          = {http://dx.doi.org/10.1074/jbc.M115.685750},
  volume       = {291},
  year         = {2016},
}