SARS-CoV-2 Nsp1 suppresses the canonical NF-κB pathway by promoting ubiquitin-dependent degradation of TAK1 kinase.

Immunoregulatory proteins expressed by SARS-CoV-2 interfere with host antiviral defences in infected cells and play critical roles in the pathogenesis and clinical manifestations of COVID-19. Here, we established a prediction algorithm by integrating a pretrained protein-language model and gene weights in immune-related pathways to quantify perturbations of SARS-CoV-2 proteins in host immunity. The results revealed that the canonical NF-κB pathway was dynamically regulated by SARS-CoV-2 infection and that nonstructural protein 1 (Nsp1) significantly suppressed the activation of the NF-κB pathway by other viral proteins and proinflammatory cytokines, such as IL-1β. Nsp1 binds to TAK1 at the TAB1-binding domain, promoting TRIM21-mediated K48-linked ubiquitination and subsequent proteasomal protein degradation, leading to the inactivation of the NF-κB signalling pathway. This work presents a novel framework to identify viral immunoregulators at the pathway level and provides mechanistic insights into immune evasion by SARS-CoV-2.