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

Author

Listed:
  • 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
    The University of Hong Kong)

  • 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)

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.

Suggested Citation

  • 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 , 2021. "IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22941-3
    DOI: 10.1038/s41467-021-22941-3
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