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

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

Nature communications (2021-04-30)
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
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 Csn2WT/K70E mice with partially disrupted binding of IP6, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4COP1 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4COP1 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2WT/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 CRL4COP1-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP6-assisted CSN-COP1 competition. Deregulation of the IP6-CSN-CRL4COP1-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Cullin-4B antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Anti-Glutathione-S-Transferase (GST)–Peroxidase Conjugate antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution