In:
Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-04-28)
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 IP 6 , 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 IP 6 -assisted CSN-COP1 competition. Deregulation of the IP 6 -CSN-CRL4 COP1 -ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-021-22941-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2553671-0
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