ErbB3-binding protein 1 (EBP1) represses HNF4?-mediated transcription and insulin secretion in pancreatic ?-cells.

ABSTRACT: HNF4? (hepatocyte nuclear factor 4?) is one of the master regulators of pancreatic ?-cell development and function, and mutations in the HNF4? gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4? exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4? participates. Here, to find HNF4?-binding proteins in pancreatic ?-cells, we used yeast two-hybrid screening, a mammalian two-hybrid assay, and glutathione S-transferase pulldown approaches, which identified EBP1 (ErbB3-binding protein 1) as a factor that binds HNF4? in a LXXLL motif-mediated manner. In the ?-cells, EBP1 suppressed the expression of HNF4? target genes that are implicated in insulin secretion, which is impaired in HNF4? mutation-driven diabetes. The crystal structure of the HNF4? ligand-binding domain in complex with a peptide harboring the EBP1 LXXLL motif at 3.15Å resolution hinted at the molecular basis of the repression. The details of the structure suggested that EBP1's LXXLL motif competes with HNF4? coactivators for the same binding pocket and thereby prevents recruitment of additional transcriptional coactivators. These findings provide further evidence that EBP1 plays multiple cellular roles and is involved in nuclear receptor-mediated gene regulation. Selective disruption of the HNF4?-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4? activities and thereby improve insulin secretion in ?-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders.

SUBMITTER: Han EH 

PROVIDER: S-EPMC6755798 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature