Bibliographic Details
| Title: |
HSC70 coordinates COP9 signalosome and SCF ubiquitin ligase activity to enable a prompt stress response. |
| Authors: |
Nishimura, Shunsuke, Kioka, Hidetaka, Ding, Shan, Hakui, Hideyuki, Shinomiya, Haruki, Tanabe, Kazuya, Hitsumoto, Tatsuro, Matsuoka, Ken, Kato, Hisakazu, Tsukamoto, Osamu, Asano, Yoshihiro, Takashima, Seiji, Enchev, Radoslav I, Sakata, Yasushi |
| Source: |
EMBO Reports; Mar2025, Vol. 26 Issue 5, p1344-1366, 23p |
| 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. Synopsis: HSC70 enables a rapid stress response by alternately regulating the activities of SCF ubiquitin ligase and COP9 signalosome (CSN) in a substrate-dependent manner. HSC70 enhances CSN deneddylation activity under basal conditions and enhances ubiquitination activity of neddylated SCF under SCF-activated conditions. HSC70 enhances CSN deneddylation activity under basal conditions and increases the ubiquitination activity of neddylated SCF under SCF-activated conditions. The presence or absence of SCF substrates regulates the alternative interaction between HSC70 and CSN or neddylated SCF. Knockdown of HSC70 reduces SCF-mediated substrate ubiquitination, leading to increased cellular vulnerability to ultraviolet irradiation. HSC70 enables a rapid stress response by alternately regulating the activities of SCF ubiquitin ligase and COP9 signalosome (CSN) in a substrate-dependent manner. HSC70 enhances CSN deneddylation activity under basal conditions and enhances ubiquitination activity of neddylated SCF under SCF-activated conditions. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
