IP-assisted CSN-COP1 Competition Regulates a CRL4-ETV5 Proteolytic Checkpoint to Safeguard Glucose-induced Insulin Secretion

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Apr 29

PMID 33911083

Citations 10

Authors

Hong Lin

Yuan Yan

Yifan Luo

Wing Yan So

Xiayun Wei

Xiaozhe Zhang

Xiaoli Yang

Jun Zhang

Yang Su

Xiuyan Yang

Bobo Zhang

Kangjun Zhang

Nan Jiang

Billy Kwok Chong Chow

Weiping Han

Fengchao Wang

Feng Rao

Affiliations

Soon will be listed here.

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 mice with partially disrupted binding of IP, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2, 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-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP-assisted CSN-COP1 competition. Deregulation of the IP-CSN-CRL4-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.

Citing Articles

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