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SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy
Chao Sui1, Tongyang Xiao2,3, Shengyuan Zhang2,3
1Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
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.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helicase NSP13 blocks type I interferon production by degrading TBK1 via autophagy. This mechanism helps SARS-CoV-2 evade the host immune response, offering insights into COVID-19 pathogenesis.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, causing COVID-19, is linked to impaired host interferon (IFN) responses.
- The precise mechanisms by which SARS-CoV-2 antagonizes the host IFN system remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which SARS-CoV-2 interferes with the host type I IFN production.
- To investigate the role of SARS-CoV-2 helicase NSP13 in antagonizing the host innate immune response.
Main Methods:
- Investigated the interaction between SARS-CoV-2 NSP13 and TANK-binding kinase 1 (TBK1).
- Utilized genetic knockout (Beclin1) and pharmacological inhibition to assess the role of autophagy in NSP13-mediated TBK1 degradation.
- Examined the recruitment of TBK1 to p62 and observed degradation and aggregation in infected cells (HEK-293T, HeLa, HeLa-ACE2, Calu3).
Main Results:
- SARS-CoV-2 helicase NSP13 was found to directly target TBK1 for degradation, thereby inhibiting type I IFN production.
- Inhibition of autophagy, either genetically or pharmacologically, rescued NSP13-mediated TBK1 degradation.
- NSP13 was shown to recruit TBK1 to p62, facilitating its autophagic degradation; TBK1 and p62 degradation and p62 aggregation were observed in SARS-CoV-2 infected cells.
Conclusions:
- SARS-CoV-2 NSP13 inhibits type I IFN production by hijacking the host autophagic pathway to degrade TBK1 via p62.
- This mechanism allows SARS-CoV-2 to evade the host innate immune system, providing crucial insights into viral pathogenesis and transmission.
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