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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to NF-κB 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-κB signaling. Nsp14 caused the nuclear translocation of NF-κB 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), which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and identified that IMPDH2 knockdown or chemical inhibition using ribavirin (RIB) and mycophenolic acid (MPA) abolishes Nsp14- mediated NF-κB activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-κB signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-κB activation through IMPDH2 to promote viral infection. Copyright © 2022 Li, Kenney, Park, Fiches, Liu, Zhou, Biswas, Zhao, Que, Santoso, Martinez-Sobrido, Yount and Zhu.

Citation

Tai-Wei Li, Adam D Kenney, Jun-Gyu Park, Guillaume N Fiches, Helu Liu, Dawei Zhou, Ayan Biswas, Weiqiang Zhao, Jianwen Que, Netty Santoso, Luis Martinez-Sobrido, Jacob S Yount, Jian Zhu. SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling. Frontiers in immunology. 2022;13:1007089

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PMID: 36177032

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