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

  • PLoS Pathog. 2026 May 4;22(5):e1014191. doi: 10.1371/journal.ppat.1014191.
Han-Cheng Wei  1  2 ,  Qingxin Yang  1 ,  Hong Yang  1 ,  Yu-Hang Wang  1 ,  Kai Wang  3 ,  Kepan Linghu  1 ,  Natacha S Ogando  4 ,  Xiaoya Huang  5 ,  Eric J Snijder  4 ,  Yu Zhong  1  2 ,  Yu Chen  1  2 ,  Quan Yuan  3 ,  Lu Chen  6 ,  Jing-Wen Lin  1  2
Affiliations
  • 1. Center of Infectious Diseases and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2. Center for Biological and Translational Research, Biosafety Laboratory of West China Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health & School of Life Sciences, Xiamen University, Xiamen, China.
  • 4. Molecular Virology Laboratory, Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands.
  • 5. State Key Laboratory of Virology, RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
  • 6. Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
PMID: 42081588 DOI: 10.1371/journal.ppat.1014191
Abstract

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.

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