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

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.

Endomembrane remodeling in SARS-CoV-2 infection

“…Inhibiting autophagy restores MHC-I expression in ORF8-expressing cells ( Zhang et al, 2021b ). NSP13 promotes autophagic degradation of TANK-binding kinase 1 (TBK1) by targeting it to the autophagy substrate p62 ( Sui et al, 2022 ). Removal of TBK1 inhibits type I interferon (IFN-I) production ( Sui et al, 2022 ).…”

Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases

“…Consequently, H7N9 PB1 protein-mediated degradation of MAVS leads to lessened RIG-I-MAVS IFN signaling and enhanced H7N9 infection ( Zeng et al, 2021 ). SARS-CoV-2 helicase NSP13 can promote the autophagic degradation of TBK1, the central kinase in IFN pathway in cooperation with cargo receptor p62, thus in turn inhibiting IFN productions ( Sui et al, 2022 ). Besides restricting the generation of type I IFN, viruses may also enforce selective autophagy to further soften IFN signal transduction.…”

The Evolutionary Dance between Innate Host Antiviral Pathways and SARS-CoV-2

“…Nsp12 is the main component of RdRp, but has also shown inhibitory effects on the IFN-I pathway [ 114 ]. Nsp13 is an RNA helicase that targets TBK1 and TBKBP1, components of the innate immune system [ 94 , 109 , 114 , 115 , 116 ]. Nsp13 also interferes with the NF-κB pathway by interacting with TLE1, TLE3, and TLE5 [ 94 , 115 ].…”