Poster abstracts
Poster number 83 submitted by Tai-Wei Li
SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling
Tai-Wei Li (Department of Pathology, OSUMC), Adam D. Kenney (Department of Microbial Infection and Immunity, OSUMC), Jun-Gyu Park (Texas Biomedical Research Institute, San Antonio, TX ), Jianwen Que (Department of Medicine, Columbia University Medical Center, New York, ), Luis Martinez-Sobrido (Texas Biomedical Research Institute, San Antonio, TX ), Jacob S. Yount (Department of Microbial Infection and Immunity, OSUMC)
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, IMDPH2 inhibitors (RIB, MPA) or NF-κB inhibitors (bortezomib, BAY 11-7082) restricted SARS-CoV-2 infection, indicating that IMDPH2-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.
References:
Zaffagni M, Harris JM, Patop IL, Pamudurti NR, Nguyen S, Kadener S. 2022. SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Elife 11.
Keywords: SARS-CoV-2, Nsp14, NF-kB