SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1

Abstract

Background SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling. Results In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1. Conclusion SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1.

Conjunctival epithelial cells resist productive SARS-CoV-2 infection

“…Notably, in both superficial and suprabasal conjunctival epithelial cells, there was some evidence of suppression of paracrine type I and III IFN signaling (Figures 6B and 6C), extending recently published findings (Xia et al, 2020;Park and Iwasaki, 2020;Fung et al, 2021;Decker, 2021), suggestive of viral evasion of IFN signaling in bystander cells. It is not clear whether this is due to a paracrine effect of SARS-CoV-2 itself or an indirect consequence of other host signals, such as TNF, which is recognized to suppress IFN responses in certain contexts (Banchereau et al, 2004).…”

Infectious Bronchitis Virus Nsp14 Degrades JAK1 to Inhibit the JAK-STAT Signaling Pathway in HD11 Cells

“…SARS-CoV-2 Nsp14 induces lysosomal degradation of IFNAR1, an essential receptor for type I IFN, thereby preventing the activation of STAT transcription factors [ 37 ]. SARS-CoV-2 Nsp13 interacts with STAT1 to prevent JAK1-induced STAT1 phosphorylation [ 48 , 49 ]. Our assays revealed that IBV Nsp14 interacted with chJAK1 to reduce chJAK1 protein levels, but not the gene levels.…”

Coronaviral Infection and Interferon Response: The Virus-Host Arms Race and COVID-19

“…By disrupting protein trafficking, these two nsps affect cytokine secretion and MHC-I recycling and induce significant reduction of the immune response [ 76 ]. The nsp13 protein block the phosphorylation of transcription factor STAT1 [ 116 ]. Nsp14 inhibits IFNs signaling differently by facilitating lysosomal degradation of the essential interferon receptor IFNAR1.…”