SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-kappa B signaling

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), which is known to regulate NF-kappa B 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-kappa B activation and cytokine induction. Furthermore, IMPDH2 inhibitors (RIB, MPA) or NF-kappa B inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMPDH2-mediated activation of NF-kappa B signaling is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in inducing NF-kappa B activation through IMPDH2 to promote viral infection.