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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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; Urano, Fumihiko; Mills, Jason C.

I: Journal of Biological Chemistry, Vol. 291, Nr. 12, 2016, s. 6146-6157.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Moore, Benjamin D ; Jin, Ramon U ; Lo, Heiyong ; Jung, Min ; Wang, Haiyan ; Battle, Michele A ; Wollheim, Claes ; Urano, Fumihiko ; Mills, Jason C. / Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function. I: Journal of Biological Chemistry. 2016 ; Vol. 291, Nr. 12. s. 6146-6157.

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TY - JOUR

T1 - Transcriptional Regulation of X-Box-Binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4α) is Vital to Beta-Cell Function.

AU - Moore, Benjamin D

AU - Jin, Ramon U

AU - Lo, Heiyong

AU - Jung, Min

AU - Wang, Haiyan

AU - Battle, Michele A

AU - Wollheim, Claes

AU - Urano, Fumihiko

AU - Mills, Jason C

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M115.685750

DO - 10.1074/jbc.M115.685750

M3 - Article

VL - 291

SP - 6146

EP - 6157

JO - Journal of Biological Chemistry

T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 12

ER -