ErbB3-binding protein 1 (EBP1) represses HNF4α-mediated transcription and insulin secretion in pancreatic β-cells. J Biol Chem 2019 Sep 20;294(38):13983-13994
Date
08/01/2019Pubmed ID
31362984Pubmed Central ID
PMC6755798DOI
10.1074/jbc.RA119.009558Scopus ID
2-s2.0-85072530867 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
HNF4α (hepatocyte nuclear factor 4α) is one of the master regulators of pancreatic β-cell development and function, and mutations in the HNF4α gene are well-known monogenic causes of diabetes. As a member of the nuclear receptor family, HNF4α exerts its gene regulatory function through various molecular interactions; however, there is a paucity of knowledge of the different functional complexes in which HNF4α participates. Here, to find HNF4α-binding proteins in pancreatic β-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 HNF4α in a LXXLL motif-mediated manner. In the β-cells, EBP1 suppressed the expression of HNF4α target genes that are implicated in insulin secretion, which is impaired in HNF4α mutation-driven diabetes. The crystal structure of the HNF4α 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 HNF4α 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 HNF4α-EBP1 interaction or tissue-specific EBP1 inactivation can enhance HNF4α activities and thereby improve insulin secretion in β-cells, potentially representing a new strategy for managing diabetes and related metabolic disorders.
Author List
Han EH, Singh P, Lee IK, Urrutia R, Chi YIAuthors
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingCarrier Proteins
DNA-Binding Proteins
Diabetes Mellitus, Type 2
Gene Expression Regulation
HeLa Cells
Hepatocyte Nuclear Factor 4
Humans
Insulin
Insulin-Secreting Cells
Promoter Regions, Genetic
Protein Binding
RNA-Binding Proteins
Transcription Factors
