The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING
The SARS-CoV-2 papain-like protease suppresses type I interferon responses by deubiquitinating STING
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DOI：
10.1126/scisignal.add0082
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发表时间：
2023-05-02
影响因子：
7.3
通讯作者：
Huang, Hao
中科院分区：
文献类型：
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作者：
Cao, Dan;Duan, Lian;Huang, Hao
具有去泛素化活性的SARS-CoV-2木瓜蛋白酶（PLpro）可抑制I型干扰素（IFN-I）抗病毒反应。我们研究了PLpro拮抗细胞抗病毒反应的机制。在HEK392T细胞中，PLpro从干扰素刺激基因（STING）的Lys289中去除k63连接的多泛素链。plpro介导的STING去泛素化破坏了STING- ikk epsilon-IRF3复合体，该复合体诱导产生ifn - β和ifn刺激的细胞因子和趋化因子。在SARS-CoV-2感染的人气道细胞中，STING激动剂diABZi和PLpro抑制剂GRL0617联合治疗可协同抑制SARS-CoV-2复制并增加IFN-I应答。七种人类冠状病毒（SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-229E、HCoV-HKU1、HCoV-OC43和HCoV-NL63）和四种SARS-CoV-2变体（α、β、γ和δ）的PLpros都与STING结合，并抑制STING刺激的HEK293T细胞中IFN-I的反应。这些发现揭示了SARS-CoV-2 PLpro如何通过STING去泛素化抑制其IFN-I信号，以及七种人类冠状病毒PLpro调节STING失调和促进病毒先天免疫逃避的一般机制。我们还确定了同时的药理学STING激活和PLpro抑制是针对SARS-CoV-2的抗病毒治疗的潜在有效策略。
The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I inter-feron (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 Lys289 of the stimulator of interferon genes (STING). PLpro-mediated deubiquitination of STING disrupted the STING-IKK epsilon-IRF3 complex that induces the production of IFN-beta and IFN-stimulated cytokines and chemokines. In human airway cells in-fected 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 (alpha, beta, gamma, and delta) all bound to STING and sup-pressed STING-stimulated IFN-I responses in HEK293T cells. These findings reveal how SARS-CoV-2 PLpro inhib-its 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 phar-macological STING activation and PLpro inhibition as a potentially effective strategy for antiviral therapy against SARS-CoV-2.