SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO

Cell Rep. 2021 Feb 16;34(7):108761. doi: 10.1016/j.celrep.2021.108761.

Jing Wu ¹, Yuheng Shi ², Xiaoyan Pan ³, Shuang Wu ¹, Ruixia Hou ¹, Yong Zhang ¹, Tiansheng Zhong ¹, Hao Tang ¹, Wei Du ¹, Luying Wang ¹, Jing Wo ¹, Jingfang Mu ³, Yang Qiu ³, Ke Yang ⁴, Lei-Ke Zhang ⁵, Bang-Ce Ye ⁶, Nan Qi ⁷

Affiliations

1 Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
2 Institutes of Biomedical Sciences, Fudan University, Shanghai 20032, China.
3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China.
4 Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang 310018, China.
5 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences (CAS), Wuhan, Hubei 430071, China. Electronic address: zhangleike@wh.iov.cn.
6 Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China. Electronic address: bcye@ecust.edu.cn.
7 Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China. Electronic address: qinan@zjut.edu.cn.

PMID: 33567255 DOI: 10.1016/j.celrep.2021.108761

Abstract

Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the Antiviral type I IFN response during SARS-CoV-2 Infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor κB (NF-κB) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IκB kinase alpha (IKKα)/β/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 Infection.

Keywords

COVID-19; RIG-I-MAVS signaling; SARS-CoV-2; innate immune response; interferon.

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