Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4? (HNF4?) Is Vital to Beta-cell Function.

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 4? (HNF4?) directly induces XBP1 expression. Mutations in HNF4? 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 HNF4? caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4? in ?-cells led to impaired ER Ca(2+) homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4?-deficient ?-cells. Our findings uncover a transcriptional relationship between HNF4? and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.

SUBMITTER: Moore BD 

PROVIDER: S-EPMC4813565 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature