| First Author | Han EH | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 38 | Pages | 13983-13994 |
| PubMed ID | 31362984 | Mgi Jnum | J:281155 |
| Mgi Id | MGI:6369340 | Doi | 10.1074/jbc.RA119.009558 |
| Citation | Han EH, et al. (2019) ErbB3-binding protein 1 (EBP1) represses HNF4alpha-mediated transcription and insulin secretion in pancreatic beta-cells. J Biol Chem 294(38):13983-13994 |
| abstractText | HNF4alpha (hepatocyte nuclear factor 4alpha) is one of the master regulators of pancreatic beta-cell development and function, and mutations in the HNF4alpha gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4alpha exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4alpha participates. Here, to find HNF4alpha-binding proteins in pancreatic beta-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 HNF4alpha in a LXXLL motif-mediated manner. In the beta-cells, EBP1 suppressed the expression of HNF4alpha target genes that are implicated in insulin secretion, which is impaired in HNF4alpha mutation-driven diabetes. The crystal structure of the HNF4alpha ligand-binding domain in complex with a peptide harboring the EBP1 LXXLL motif at 3.15A resolution hinted at the molecular basis of the repression. The details of the structure suggested that EBP1's LXXLL motif competes with HNF4alpha 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 HNF4alpha-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4alpha activities and thereby improve insulin secretion in beta-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders. |
