Cargando…
SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling
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 act...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513374/ https://www.ncbi.nlm.nih.gov/pubmed/36177032 http://dx.doi.org/10.3389/fimmu.2022.1007089 |
_version_ | 1784798048104218624 |
---|---|
author | Li, Tai-Wei Kenney, Adam D. Park, Jun-Gyu Fiches, Guillaume N. Liu, Helu Zhou, Dawei Biswas, Ayan Zhao, Weiqiang Que, Jianwen Santoso, Netty Martinez-Sobrido, Luis Yount, Jacob S. Zhu, Jian |
author_facet | Li, Tai-Wei Kenney, Adam D. Park, Jun-Gyu Fiches, Guillaume N. Liu, Helu Zhou, Dawei Biswas, Ayan Zhao, Weiqiang Que, Jianwen Santoso, Netty Martinez-Sobrido, Luis Yount, Jacob S. Zhu, Jian |
author_sort | Li, Tai-Wei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9513374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95133742022-09-28 SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling Li, Tai-Wei Kenney, Adam D. Park, Jun-Gyu Fiches, Guillaume N. Liu, Helu Zhou, Dawei Biswas, Ayan Zhao, Weiqiang Que, Jianwen Santoso, Netty Martinez-Sobrido, Luis Yount, Jacob S. Zhu, Jian Front Immunol Immunology 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. Frontiers Media S.A. 2022-09-13 /pmc/articles/PMC9513374/ /pubmed/36177032 http://dx.doi.org/10.3389/fimmu.2022.1007089 Text en Copyright © 2022 Li, Kenney, Park, Fiches, Liu, Zhou, Biswas, Zhao, Que, Santoso, Martinez-Sobrido, Yount and Zhu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Li, Tai-Wei Kenney, Adam D. Park, Jun-Gyu Fiches, Guillaume N. Liu, Helu Zhou, Dawei Biswas, Ayan Zhao, Weiqiang Que, Jianwen Santoso, Netty Martinez-Sobrido, Luis Yount, Jacob S. Zhu, Jian SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title | SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title_full | SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title_fullStr | SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title_full_unstemmed | SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title_short | SARS-CoV-2 Nsp14 protein associates with IMPDH2 and activates NF-κB signaling |
title_sort | sars-cov-2 nsp14 protein associates with impdh2 and activates nf-κb signaling |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513374/ https://www.ncbi.nlm.nih.gov/pubmed/36177032 http://dx.doi.org/10.3389/fimmu.2022.1007089 |
work_keys_str_mv | AT litaiwei sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT kenneyadamd sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT parkjungyu sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT fichesguillaumen sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT liuhelu sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT zhoudawei sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT biswasayan sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT zhaoweiqiang sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT quejianwen sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT santosonetty sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT martinezsobridoluis sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT yountjacobs sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling AT zhujian sarscov2nsp14proteinassociateswithimpdh2andactivatesnfkbsignaling |