IP 6 -assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion

• Published in: Nature communications Vol. 12; no. 1; p. 2461
• Main Authors: Lin, Hong, Yan, Yuan, Luo, Yifan, So, Wing Yan, Wei, Xiayun, Zhang, Xiaozhe, Yang, Xiaoli, Zhang, Jun, Su, Yang, Yang, Xiuyan, Zhang, Bobo, Zhang, Kangjun, Jiang, Nan, Chow, Billy Kwok Chong, Han, Weiping, Wang, Fengchao, Rao, Feng
• Format: Journal Article
• Language: English
• Published: England 28.04.2021
• Subjects: Animals; Cell Line; COP9 Signalosome Complex - metabolism; Cyclopentanes - pharmacology; Diabetes Mellitus - drug therapy; DNA-Binding Proteins - metabolism; Enzyme Inhibitors - pharmacology; Glucose - metabolism; HEK293 Cells; Humans; Hyperinsulinism - drug therapy; Insulin Secretion - genetics; Insulin Secretion - physiology; Insulin-Secreting Cells - metabolism; Mice; Mice, Inbred C57BL; Nuclear Proteins - metabolism; Obesity - drug therapy; Pyrimidines - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Transcription Factors - metabolism; Ubiquitin-Protein Ligase Complexes - metabolism; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723

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.