tetano
Editor, Senior Moderator
Sci Signal
. 2023 May 2;16(783):eadd0082.
doi: 10.1126/scisignal.add0082. Epub 2023 May 2. The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING
Dan Cao[SUP] 1 [/SUP], Lian Duan[SUP] 2 [/SUP], Bin Huang[SUP] 1 [/SUP], Yuxian Xiong[SUP] 1 [/SUP], Guoliang Zhang[SUP] 2 [/SUP], Hao Huang[SUP] 1 3 [/SUP]
Affiliations
The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I interferon (IFN-I) antiviral response. We investigated the mechanism by which PLpro antagonizes cellular antiviral responses. In HEK392T cells, PLpro removed K63-linked polyubiquitin chains from Lys[SUP]289[/SUP] of the stimulator of interferon genes (STING). PLpro-mediated deubiquitination of STING disrupted the STING-IKKε-IRF3 complex that induces the production of IFN-β and IFN-stimulated cytokines and chemokines. In human airway cells infected with SARS-CoV-2, the combined treatment with the STING agonist diABZi and the PLpro inhibitor GRL0617 resulted in the synergistic inhibition of SARS-CoV-2 replication and increased IFN-I responses. The PLpros of seven human coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) and four SARS-CoV-2 variants of concern (α, β, γ, and δ) all bound to STING and suppressed STING-stimulated IFN-I responses in HEK293T cells. These findings reveal how SARS-CoV-2 PLpro inhibits IFN-I signaling through STING deubiquitination and a general mechanism used by seven human coronaviral PLpros to dysregulate STING and to facilitate viral innate immune evasion. We also identified simultaneous pharmacological STING activation and PLpro inhibition as a potentially effective strategy for antiviral therapy against SARS-CoV-2.
. 2023 May 2;16(783):eadd0082.
doi: 10.1126/scisignal.add0082. Epub 2023 May 2. The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING
Dan Cao[SUP] 1 [/SUP], Lian Duan[SUP] 2 [/SUP], Bin Huang[SUP] 1 [/SUP], Yuxian Xiong[SUP] 1 [/SUP], Guoliang Zhang[SUP] 2 [/SUP], Hao Huang[SUP] 1 3 [/SUP]
Affiliations
- PMID: 37130168
- DOI: 10.1126/scisignal.add0082
The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I interferon (IFN-I) antiviral response. We investigated the mechanism by which PLpro antagonizes cellular antiviral responses. In HEK392T cells, PLpro removed K63-linked polyubiquitin chains from Lys[SUP]289[/SUP] of the stimulator of interferon genes (STING). PLpro-mediated deubiquitination of STING disrupted the STING-IKKε-IRF3 complex that induces the production of IFN-β and IFN-stimulated cytokines and chemokines. In human airway cells infected with SARS-CoV-2, the combined treatment with the STING agonist diABZi and the PLpro inhibitor GRL0617 resulted in the synergistic inhibition of SARS-CoV-2 replication and increased IFN-I responses. The PLpros of seven human coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) and four SARS-CoV-2 variants of concern (α, β, γ, and δ) all bound to STING and suppressed STING-stimulated IFN-I responses in HEK293T cells. These findings reveal how SARS-CoV-2 PLpro inhibits IFN-I signaling through STING deubiquitination and a general mechanism used by seven human coronaviral PLpros to dysregulate STING and to facilitate viral innate immune evasion. We also identified simultaneous pharmacological STING activation and PLpro inhibition as a potentially effective strategy for antiviral therapy against SARS-CoV-2.