The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING

Cao，Dan1; Duan，Lian2; Huang，Bin1; Xiong，Yuxian1; Zhang，Guoliang2; Huang，Hao1,3

2023

10.1126/scisignal.add0082

Science Signaling   Impact Factor & Quartile

1945-0877

1937-9145

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 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, HCoVOC43, 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.

SCI

English

Corresponding

National Natural Science Foundation of China[21977009];National Natural Science Foundation of China[32100567];National Natural Science Foundation of China[81770012];

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000988282400003

AMER ASSOC ADVANCEMENT SCIENCE

2-s2.0-85158062787

Scopus

1.State Key Laboratory of Chemical Oncogenomics,Guangdong Provincial Key Laboratory of Chemical Genomics,Laboratory of Structural Biology and Drug Discovery,Laboratory of Ubiquitination and Targeted Therapy,School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen,518055,China
2.National Clinical Research Center for Infectious Diseases,Shenzhen Third People’s Hospital,Southern University of Science and Technology,Shenzhen,518112,China
3.Institute of Chemical Biology,Shenzhen Bay Laboratory,Shenzhen,Guangdong,518132,China

Cao，Dan,Duan，Lian,Huang，Bin,et al. The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING[J]. Science Signaling,2023,16(783).

Cao，Dan,Duan，Lian,Huang，Bin,Xiong，Yuxian,Zhang，Guoliang,&Huang，Hao.(2023).The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING.Science Signaling,16(783).

Cao，Dan,et al."The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING".Science Signaling 16.783(2023).