1. SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling.
- Author
-
Tai-Wei Li, Kenney, Adam D., Park, Jun-Gyu, Fiches, Guillaume N., Liu, Helu, Zhou, Dawei, Biswas, Ayan, Weiqiang Zhao, Jianwen Que, Santoso, Netty, Martinez-Sobrido, Luis, Yount, Jacob S., and Jian Zhu
- Subjects
SARS-CoV-2 ,RIBAVIRIN ,BORTEZOMIB ,COVID-19 - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF