Cargando…

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Taiwei, Kenney, Adam D., Liu, Helu, Fiches, Guillaume N., Zhou, Dawei, Biswas, Ayan, Que, Jianwen, Santoso, Netty, Yount, Jacob S., Zhu, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168382/
https://www.ncbi.nlm.nih.gov/pubmed/34075374
http://dx.doi.org/10.1101/2021.05.26.445787
_version_ 1783701871946366976
author Li, Taiwei
Kenney, Adam D.
Liu, Helu
Fiches, Guillaume N.
Zhou, Dawei
Biswas, Ayan
Que, Jianwen
Santoso, Netty
Yount, Jacob S.
Zhu, Jian
author_facet Li, Taiwei
Kenney, Adam D.
Liu, Helu
Fiches, Guillaume N.
Zhou, Dawei
Biswas, Ayan
Que, Jianwen
Santoso, Netty
Yount, Jacob S.
Zhu, Jian
author_sort Li, Taiwei
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) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found 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) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB.
format Online
Article
Text
id pubmed-8168382
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-81683822021-06-02 SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation Li, Taiwei Kenney, Adam D. Liu, Helu Fiches, Guillaume N. Zhou, Dawei Biswas, Ayan Que, Jianwen Santoso, Netty Yount, Jacob S. Zhu, Jian bioRxiv Article 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) protein, which is known to regulate NF-κB signaling. We confirmed the Nsp14-IMPDH2 protein interaction and found 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) efficiently blocked SARS-CoV-2 infection, indicating that IMDPH2, and possibly NF-κB signaling, is beneficial to viral replication. Overall, our results identify a novel role of SARS-CoV-2 Nsp14 in causing the activation of NF-κB. Cold Spring Harbor Laboratory 2021-05-26 /pmc/articles/PMC8168382/ /pubmed/34075374 http://dx.doi.org/10.1101/2021.05.26.445787 Text en https://creativecommons.org/licenses/by-nc/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Li, Taiwei
Kenney, Adam D.
Liu, Helu
Fiches, Guillaume N.
Zhou, Dawei
Biswas, Ayan
Que, Jianwen
Santoso, Netty
Yount, Jacob S.
Zhu, Jian
SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title_full SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title_fullStr SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title_full_unstemmed SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title_short SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation
title_sort sars-cov-2 nsp14 activates nf-κb signaling and induces il-8 upregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168382/
https://www.ncbi.nlm.nih.gov/pubmed/34075374
http://dx.doi.org/10.1101/2021.05.26.445787
work_keys_str_mv AT litaiwei sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT kenneyadamd sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT liuhelu sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT fichesguillaumen sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT zhoudawei sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT biswasayan sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT quejianwen sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT santosonetty sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT yountjacobs sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation
AT zhujian sarscov2nsp14activatesnfkbsignalingandinducesil8upregulation