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 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.

Mediators of insulin signalling are targets of cullin-RING ubiquitin ligases (CRL) that mediate protein degradation, but the role of protein degradation in insulin signalling is incompletely understood. Here, the authors identified a glucose-responsive CRL4-COP1-ETV5 proteolytic axis that promotes insulin secretion, and is inhibited under hypoglycemia.