tetano
Editor, Senior Moderator
J Biol Chem
. 2023 Apr 1;104668.
doi: 10.1016/j.jbc.2023.104668. Online ahead of print.
Heat shock protein 90 facilitates SARS-CoV-2 structural protein-mediated virion assembly and promotes virus-induced pyroptosis
Zhuangzhuang Zhao[SUP] 1 [/SUP], Ling-Dong Xu[SUP] 2 [/SUP], Fei Zhang[SUP] 2 [/SUP], Qi-Zhang Liang[SUP] 3 [/SUP], Yajuan Jiao[SUP] 1 [/SUP], Fang-Shu Shi[SUP] 1 [/SUP], Biao He[SUP] 4 [/SUP], Pinglong Xu[SUP] 5 [/SUP], Yao-Wei Huang[SUP] 6 [/SUP]
Affiliations
Abstract
Inhibition of heat shock protein 90 (Hsp90), a prominent molecular chaperone, effectively limits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but little is known about any interaction between Hsp90 and SARS-CoV-2 proteins. Here, we systematically analyzed the effects of the chaperone isoforms Hsp90α and Hsp90β on individual SARS-CoV-2 viral proteins. Five SARS-CoV-2 proteins, namely nucleocapsid (N), membrane (M), and accessory proteins Orf3, Orf7a, and Orf7b were found to be novel clients of Hsp90β in particular. Pharmacological inhibition of Hsp90 with 17-DMAG results in N protein proteasome-dependent degradation. Hsp90 depletion-induced N protein degradation is independent of CHIP, a ubiquitin E3 ligase previously identified for Hsp90 client proteins, but alleviated by FBXO10, an E3 ligase identified by subsequent siRNA screening. We also provide evidence that Hsp90 depletion may suppress SARS-CoV-2 assembly partially through induced M or N degradation. Additionally, we found that GSDMD-mediated pyroptotic cell death triggered by SARS-CoV-2 was mitigated by inhibition of Hsp90. These findings collectively highlight a beneficial role for targeting of Hsp90 during SARS-CoV-2 infection, directly inhibiting virion production and reducing inflammatory injury by preventing the pyroptosis that contributes to severe SARS-CoV-2 disease.
Keywords: Degradation; E3 ligase; Gasdermin D; Hsp90; Nucleoprotein; Pyroptosis; SARS-CoV-2.
. 2023 Apr 1;104668.
doi: 10.1016/j.jbc.2023.104668. Online ahead of print.
Heat shock protein 90 facilitates SARS-CoV-2 structural protein-mediated virion assembly and promotes virus-induced pyroptosis
Zhuangzhuang Zhao[SUP] 1 [/SUP], Ling-Dong Xu[SUP] 2 [/SUP], Fei Zhang[SUP] 2 [/SUP], Qi-Zhang Liang[SUP] 3 [/SUP], Yajuan Jiao[SUP] 1 [/SUP], Fang-Shu Shi[SUP] 1 [/SUP], Biao He[SUP] 4 [/SUP], Pinglong Xu[SUP] 5 [/SUP], Yao-Wei Huang[SUP] 6 [/SUP]
Affiliations
- PMID: 37011862
- DOI: 10.1016/j.jbc.2023.104668
Abstract
Inhibition of heat shock protein 90 (Hsp90), a prominent molecular chaperone, effectively limits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but little is known about any interaction between Hsp90 and SARS-CoV-2 proteins. Here, we systematically analyzed the effects of the chaperone isoforms Hsp90α and Hsp90β on individual SARS-CoV-2 viral proteins. Five SARS-CoV-2 proteins, namely nucleocapsid (N), membrane (M), and accessory proteins Orf3, Orf7a, and Orf7b were found to be novel clients of Hsp90β in particular. Pharmacological inhibition of Hsp90 with 17-DMAG results in N protein proteasome-dependent degradation. Hsp90 depletion-induced N protein degradation is independent of CHIP, a ubiquitin E3 ligase previously identified for Hsp90 client proteins, but alleviated by FBXO10, an E3 ligase identified by subsequent siRNA screening. We also provide evidence that Hsp90 depletion may suppress SARS-CoV-2 assembly partially through induced M or N degradation. Additionally, we found that GSDMD-mediated pyroptotic cell death triggered by SARS-CoV-2 was mitigated by inhibition of Hsp90. These findings collectively highlight a beneficial role for targeting of Hsp90 during SARS-CoV-2 infection, directly inhibiting virion production and reducing inflammatory injury by preventing the pyroptosis that contributes to severe SARS-CoV-2 disease.
Keywords: Degradation; E3 ligase; Gasdermin D; Hsp90; Nucleoprotein; Pyroptosis; SARS-CoV-2.