IRF2BP2 is a novel HNF4α co-repressor: Its role in gluconeogenic gene regulation via biochemically labile interaction

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) has essential roles in controlling the expression of a variety of genes involved in key metabolic pathways, including gluconeogenesis in the liver. The mechanistic and physiological significance of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) for HNF4 alpha-mediated transcriptional activation models for gluconeogenic genes is well characterized. However, the transcriptional repression of HNF4 alpha for those genes remains to be examined. In this study, we applied novel proteomic techniques to evaluate the interactions of HNF4 alpha, including those with biochemically labile binding proteins. Based upon our experiments, we identified interferon regulatory factor 2 binding protein 2 (IRF2BP2) as a novel HNF4 alpha co-repressor. This interaction could not be detected by conventional immunoprecipitation. IRF2BP2 repressed the transcriptional activity of HNF4 alpha dependent on its E3 ubiquitin ligase activity. Deficiency of the IRF2BP2 gene in HepG2 cells induced gluconeogenic genes comparable to that of forskolin-treated wild-type HepG2 cells. Together, these results suggest that IRF2BP2 represents a novel class of nuclear receptor co-regulator. (C) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study investigates the interaction between HNF4α and IRF2BP2 and their regulatory effects on gluconeogenic gene expression. The experiments reveal that IRF2BP2 functions as a novel co-repressor of HNF4α, suppressing its transcriptional activity through its E3 ubiquitin ligase activity. This finding uncovers a new characteristic of nuclear receptor co-regulators.