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

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 CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4^COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP₆-assisted CSN-COP1 competition. Deregulation of the IP₆-CSN-CRL4^COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.