Abstract
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.
Keywords: IL-8; IMPDH2; NF-κB; Nsp14; SARS-CoV-2; mycophenolic acid; ribavirin.
【저자키워드】 SARS-CoV-2, nsp14, IL-8, NF-κB, ribavirin., mycophenolic acid, IMPDH2, 【초록키워드】 viral infection, coronavirus, IL-6, SARS-COV-2 infection, Infection, cytokine, ribavirin, Protein, viral replication, pro-inflammatory cytokines, inhibitor, mechanism, proteomic, COVID-19 patients, Interaction, regulate, acute respiratory syndrome, Activation, NF-κB activation, nuclear translocation, upregulation, knockdown, SARS-CoV-2 infected cells, NF-κB signaling, Host, identify, occurred, caused, contribute, promote, p65, bortezomib, lung tissue sample, the SARS-CoV-2, 【제목키워드】 Protein, NF-κB signaling, activate,