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bioRxiv · 10.1101/2021.05.26.445787

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

Li, T.-W.·Kenney, A. D.·Liu, H.·Fiches, G. N.·Zhou, D.·Biswas, A.·Que, J.·Santoso, N.·Yount, J. S.·Zhu, J.
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-{kappa}B activation and induction of pro-inflammatory cytokines, though the underlying mechanism for this activation is not fully understood. Our results reveal that the SARS-CoV-2 Nsp14 protein contributes to the viral activation of NF-{kappa}B signaling. Nsp14 caused the nuclear translocation of NF-{kappa}B p65. Nsp14 induced the upregulation of IL-6 and IL-8, which also occurred in SARS-CoV-2 infected cells. IL-8 upregulation was further confirmed in lung tissue samples from COVID-19 patients. A previous proteomic screen identified the putative interaction of Nsp14 with host Inosine-5-monophosphate dehydrogenase 2 (IMPDH2) protein, which is known to regulate NF-{kappa}B signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14-mediated NF-{kappa}B activation and cytokine induction. Furthermore, IMDPH2 inhibitors (RIB, MPA) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-{kappa}B signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-{kappa}B.

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Li, T.-W., Kenney, A. D., Liu, H., Fiches, G. N., Zhou, D., Biswas, A., Que, J., Santoso, N., Yount, J. S., Zhu, J.. 2021-05-26. SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation. https://doi.org/10.1101/2021.05.26.445787

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