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- Publisher Website: 10.1038/s41467-021-22941-3
- Scopus: eid_2-s2.0-85105041918
- PMID: 33911083
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Article: IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion
Title | IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion |
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Authors | |
Issue Date | 2021 |
Publisher | Nature Research: Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html |
Citation | Nature Communications, 2021, v. 12 n. 1, p. article no. 2461 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/305123 |
ISSN | 2023 Impact Factor: 14.7 2023 SCImago Journal Rankings: 4.887 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Lin, H | - |
dc.contributor.author | Yan, Y | - |
dc.contributor.author | LUO, Y | - |
dc.contributor.author | So, WY | - |
dc.contributor.author | Wei, X | - |
dc.contributor.author | Zhang, X | - |
dc.contributor.author | Yang, X | - |
dc.contributor.author | Zhang, J | - |
dc.contributor.author | Su, Y | - |
dc.contributor.author | Yang, X | - |
dc.contributor.author | Zhang, B | - |
dc.contributor.author | Zhang, K | - |
dc.contributor.author | Jiang, N | - |
dc.contributor.author | Chow, BKC | - |
dc.contributor.author | Han, W | - |
dc.contributor.author | Wang, F | - |
dc.contributor.author | Rao, F | - |
dc.date.accessioned | 2021-10-05T02:40:03Z | - |
dc.date.available | 2021-10-05T02:40:03Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Nature Communications, 2021, v. 12 n. 1, p. article no. 2461 | - |
dc.identifier.issn | 2041-1723 | - |
dc.identifier.uri | http://hdl.handle.net/10722/305123 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.publisher | Nature Research: Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html | - |
dc.relation.ispartof | Nature Communications | - |
dc.rights | Nature Communications. Copyright © Nature Research: Fully open access journals. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion | - |
dc.type | Article | - |
dc.identifier.email | Chow, BKC: bkcc@hku.hk | - |
dc.identifier.authority | Chow, BKC=rp00681 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1038/s41467-021-22941-3 | - |
dc.identifier.pmid | 33911083 | - |
dc.identifier.pmcid | PMC8080631 | - |
dc.identifier.scopus | eid_2-s2.0-85105041918 | - |
dc.identifier.hkuros | 326282 | - |
dc.identifier.volume | 12 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | article no. 2461 | - |
dc.identifier.epage | article no. 2461 | - |
dc.identifier.isi | WOS:000647110400008 | - |
dc.publisher.place | United Kingdom | - |