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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-\u03baB pathway was dynamically regulated by SARS-CoV-2 infection and that nonstructural protein 1 (Nsp1) significantly suppressed the activation of the NF-\u03baB pathway by other viral proteins and proinflammatory cytokines, such as IL-1\u03b2. 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-\u03baB 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014191","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:42:42Z","timestamp":1777916562000},"page":"e1014191","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["SARS-CoV-2 Nsp1 suppresses the canonical NF-\u03baB pathway by promoting ubiquitin-dependent degradation of TAK1 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