HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response

The SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex plays a protective role against external stress, such as ultraviolet irradiation. The emergence of substrates activates SCF through neddylation, the covalent attachment of ubiquitin-like protein NEDD8 to CUL1. After substrate degradation, SCF is inactivated through deneddylation by COP9-signalosome (CSN), a solo enzyme that can deneddylate SCF. How the activity of CSN and SCF is coordinated within the cell is not fully understood. Here, we find that heat-shock cognate 70 (HSC70) chaperone coordinates SCF and CSN activation dependent on the neddylation status and substrate availability. Under basal conditions and low substrate availability, HCS70 directly enhances CSN deneddylation activity, thereby reducing SCF activity. Under SCF-activated conditions, HSC70 interacts with neddylated SCF and enhances its ubiquitination activity. The alternative interaction between HSC70 and CSN or neddylated SCF is regulated by the presence or absence of SCF substrates. The knockdown of HSC70 decreases SCF-mediated substrate ubiquitination, resulting in vulnerability against ultraviolet irradiation. Our work demonstrates the pivotal role of HSC70 in the alternative activation of CSN deneddylation and SCF substrate ubiquitination, which enables a prompt stress response.

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Publication Details

Journal
EMBO Reports
Published
2025-02-06
DOI
https://doi.org/10.1038/s44319-025-00376-x
Citations
3
Primary Topic
Heat shock proteins research
Type
article
Field-Weighted Citation Impact
2.42

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article

HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response

Hideyuki Hakui, Haruki Shinomiya, Yoshihiro Asano, Yasushi Sakata et al.
3 citations
EMBO Reports
Heat shock proteins research
2.42
article

HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response

Hideyuki Hakui, Haruki Shinomiya, Yoshihiro Asano, Yasushi Sakata, Kazuya Tanabe, Radoslav I. Enchev, Hisakazu Kato, Osamu Tsukamoto, Hidetaka Kioka, Tatsuro Hitsumoto, Shunsuke Nishimura, Ken Matsuoka, Shan Ding, Seiji Takashima
article en
3 citations

Abstract

The SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex plays a protective role against external stress, such as ultraviolet irradiation. The emergence of substrates activates SCF through neddylation, the covalent attachment of ubiquitin-like protein NEDD8 to CUL1. After substrate degradation, SCF is inactivated through deneddylation by COP9-signalosome (CSN), a solo enzyme that can deneddylate SCF. How the activity of CSN and SCF is coordinated within the cell is not fully understood. Here, we find that heat-shock cognate 70 (HSC70) chaperone coordinates SCF and CSN activation dependent on the neddylation status and substrate availability. Under basal conditions and low substrate availability, HCS70 directly enhances CSN deneddylation activity, thereby reducing SCF activity. Under SCF-activated conditions, HSC70 interacts with neddylated SCF and enhances its ubiquitination activity. The alternative interaction between HSC70 and CSN or neddylated SCF is regulated by the presence or absence of SCF substrates. The knockdown of HSC70 decreases SCF-mediated substrate ubiquitination, resulting in vulnerability against ultraviolet irradiation. Our work demonstrates the pivotal role of HSC70 in the alternative activation of CSN deneddylation and SCF substrate ubiquitination, which enables a prompt stress response.

EMBO ReportsVol. 26(5)
Hyogo Medical University (JP), King's College London (GB), The Francis Crick Institute (GB), National Cerebral and Cardiovascular Center (JP), Osaka International Cancer Institute (JP), Hyogo University (JP), The University of Osaka (JP)
Takeda Science Foundation, Japan Agency for Medical Research and Development, Wellcome Trust, Francis Crick Institute, Cancer Research UK, Osaka Medical Research Foundation for Intractable Diseases, SENSHIN Medical Research Foundation, Japan Heart Foundation, Medical Research Council, Japan Society for the Promotion of Science, Fusion Oriented REsearch for disruptive Science and Technology
Clean water and sanitation
Openalex Percentile: Top 13%
Heat shock proteins research
2.42
DOIOpen Access PDFOpenAlex
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