tetano
Editor, Senior Moderator
Cell Rep
. 2021 Feb 3;108761.
doi: 10.1016/j.celrep.2021.108761. Online ahead of print.
SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO
Jing Wu[SUP] 1 [/SUP], Yuheng Shi[SUP] 2 [/SUP], Xiaoyan Pan[SUP] 3 [/SUP], Shuang Wu[SUP] 1 [/SUP], Ruixia Hou[SUP] 1 [/SUP], Yong Zhang[SUP] 1 [/SUP], Tiansheng Zhong[SUP] 1 [/SUP], Hao Tang[SUP] 1 [/SUP], Wei Du[SUP] 1 [/SUP], Luying Wang[SUP] 1 [/SUP], Jing Wo[SUP] 1 [/SUP], Jingfang Mu[SUP] 3 [/SUP], Yang Qiu[SUP] 3 [/SUP], Ke Yang[SUP] 4 [/SUP], Lei-Ke Zhang[SUP] 5 [/SUP], Bang-Ce Ye[SUP] 6 [/SUP], Nan Qi[SUP] 7 [/SUP]
Affiliations
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.
. 2021 Feb 3;108761.
doi: 10.1016/j.celrep.2021.108761. Online ahead of print.
SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO
Jing Wu[SUP] 1 [/SUP], Yuheng Shi[SUP] 2 [/SUP], Xiaoyan Pan[SUP] 3 [/SUP], Shuang Wu[SUP] 1 [/SUP], Ruixia Hou[SUP] 1 [/SUP], Yong Zhang[SUP] 1 [/SUP], Tiansheng Zhong[SUP] 1 [/SUP], Hao Tang[SUP] 1 [/SUP], Wei Du[SUP] 1 [/SUP], Luying Wang[SUP] 1 [/SUP], Jing Wo[SUP] 1 [/SUP], Jingfang Mu[SUP] 3 [/SUP], Yang Qiu[SUP] 3 [/SUP], Ke Yang[SUP] 4 [/SUP], Lei-Ke Zhang[SUP] 5 [/SUP], Bang-Ce Ye[SUP] 6 [/SUP], Nan Qi[SUP] 7 [/SUP]
Affiliations
- 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.