2. Academic Validation
  3. HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response

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

  • EMBO Rep. 2025 Feb 6. doi: 10.1038/s44319-025-00376-x.
Shunsuke Nishimura 1,  Hidetaka Kioka 2,  Shan Ding 3 4,  Hideyuki Hakui 1,  Haruki Shinomiya 1,  Kazuya Tanabe 1,  Tatsuro Hitsumoto 5,  Ken Matsuoka 5,  Hisakazu Kato 5,  Osamu Tsukamoto 5 6,  Yoshihiro Asano 1 7,  Seiji Takashima 5 8,  Radoslav I Enchev 3,  Yasushi Sakata 1
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
  • 2 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. kioka@cardiology.med.osaka-u.ac.jp.
  • 3 The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 4 Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
  • 5 Department of Medical Biochemistry, Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan.
  • 6 Department of Biochemistry, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan.
  • 7 Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
  • 8 The Osaka Medical Research Foundation for Intractable Diseases, Sumiyoshi-ku, Osaka, Japan.
PMID: 39915298 DOI: 10.1038/s44319-025-00376-x
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.

Keywords

COP9 Signalosome; HSC70; Proteostasis; SCF Ubiquitin Ligase; Stress Response.

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