SARS-CoV-2 ORF9b Inhibits RIG-I-MAVS Antiviral Signaling by Interrupting K63-Linked Ubiquitination of NEMO

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

COVID-19 is a current global health threat caused by the novel coronavirus SARS-CoV-2. Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferons (IFNs) 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 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 NF-κB essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical 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.