SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy

  • J Immunol. 2022 Feb 1;208(3):753-761. doi: 10.4049/jimmunol.2100684.
Chao Sui  1 ,  Tongyang Xiao  2  3 ,  Shengyuan Zhang  2  3 ,  Hongxiang Zeng  2  3 ,  Yi Zheng  1 ,  Bingyu Liu  1 ,  Gang Xu  4  3 ,  Chengjiang Gao  5 ,  Zheng Zhang  4  3  6  7
Affiliations
  • 1. Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 2. Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, China.
  • 3. The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province, China.
  • 4. Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong Province, China; [email protected] [email protected] [email protected].
  • 5. Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China; [email protected] [email protected] [email protected].
  • 6. Shenzhen Research Center for Communicable Disease Diagnosis and Treatment of Chinese Academy of Medical Science, Shenzhen, Guangdong Province, China; and.
  • 7. Guangdong Key laboratory for anti-infection Drug Quality Evaluation, Shenzhen, Guangdong Province, China.
PMID: 34996837 DOI: 10.4049/jimmunol.2100684
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has seriously threatened global public health. Severe COVID-19 has been reported to be associated with an impaired IFN response. However, the mechanisms of how SARS-CoV-2 antagonizes the host IFN response are poorly understood. In this study, we report that SARS-CoV-2 helicase NSP13 inhibits type I IFN production by directly targeting TANK-binding kinase 1 (TBK1) for degradation. Interestingly, inhibition of Autophagy by genetic knockout of Beclin1 or pharmacological inhibition can rescue NSP13-mediated TBK1 degradation in HEK-293T cells. Subsequent studies revealed that NSP13 recruits TBK1 to p62, and the absence of p62 can also inhibit TBK1 degradation in HEK-293T and HeLa cells. Finally, TBK1 and p62 degradation and p62 aggregation were observed during SARS-CoV-2 Infection in HeLa-ACE2 and Calu3 cells. Overall, our study shows that NSP13 inhibits type I IFN production by recruiting TBK1 to p62 for autophagic degradation, enabling it to evade the host innate immune response, which provides new insights into the transmission and pathogenesis of SARS-CoV-2 Infection.

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