Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8576690
- author
- Moore, Benjamin D ; Jin, Ramon U ; Lo, Heiyong ; Jung, Min ; Wang, Haiyan ; Battle, Michele A ; Wollheim, Claes LU ; Urano, Fumihiko and Mills, Jason C
- organization
- publishing date
- 2016-01-20
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 291
- issue
- 12
- pages
- 6146 - 6157
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:26792861
- wos:000372894200009
- scopus:84964891117
- pmid:26792861
- 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
- 2016-04-04 07:49:07
- date last changed
- 2024-04-12 19:27:30
@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 = {{American Society for Biochemistry and Molecular Biology}}, 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}}, doi = {{10.1074/jbc.M115.685750}}, volume = {{291}}, year = {{2016}}, }