IP₆-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.

ABSTRACT: COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1-CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2^WT/K70E mice with partially disrupted binding of IP₆, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4^COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4^COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2^WT/K70E, high-fat diet-treated, and ob/ob mice. The

SUBMITTER: Lin H 

PROVIDER: S-EPMC8080631 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature