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

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 and Feng Rao ()
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Hong Lin: Southern University of Science and Technology, Shenzhen
Yuan Yan: Southern University of Science and Technology, Shenzhen
Yifan Luo: Southern University of Science and Technology, Shenzhen
Wing Yan So: Technology, and Research
Xiayun Wei: Southern University of Science and Technology, Shenzhen
Xiaozhe Zhang: Southern University of Science and Technology, Shenzhen
Xiaoli Yang: Southern University of Science and Technology, Shenzhen
Jun Zhang: Southern University of Science and Technology, Shenzhen
Yang Su: Southern University of Science and Technology, Shenzhen
Xiuyan Yang: Southern University of Science and Technology, Shenzhen
Bobo Zhang: Southern University of Science and Technology, Shenzhen
Kangjun Zhang: the Third People’s Hospital of Shenzhen and the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen
Nan Jiang: the Third People’s Hospital of Shenzhen and the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen
Billy Kwok Chong Chow: The University of Hong Kong
Weiping Han: Technology, and Research
Fengchao Wang: National Institute of Biological Sciences
Feng Rao: Southern University of Science and Technology, Shenzhen

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22941-3

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