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The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway

Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be drive...

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Autores principales: McKay, Lindsay G. A., Thomas, Jordan, Albalawi, Wejdan, Fattaccioli, Antoine, Dieu, Marc, Ruggiero, Alessandra, McKeating, Jane A., Ball, Jonathan K., Tarr, Alexander W., Renard, Patricia, Pollakis, Georgios, Paxton, William A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964954/
https://www.ncbi.nlm.nih.gov/pubmed/35371105
http://dx.doi.org/10.3389/fimmu.2022.831695
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author McKay, Lindsay G. A.
Thomas, Jordan
Albalawi, Wejdan
Fattaccioli, Antoine
Dieu, Marc
Ruggiero, Alessandra
McKeating, Jane A.
Ball, Jonathan K.
Tarr, Alexander W.
Renard, Patricia
Pollakis, Georgios
Paxton, William A.
author_facet McKay, Lindsay G. A.
Thomas, Jordan
Albalawi, Wejdan
Fattaccioli, Antoine
Dieu, Marc
Ruggiero, Alessandra
McKeating, Jane A.
Ball, Jonathan K.
Tarr, Alexander W.
Renard, Patricia
Pollakis, Georgios
Paxton, William A.
author_sort McKay, Lindsay G. A.
collection PubMed
description Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be driven by host and viral genetic factors as well as HCV encoded immunomodulatory proteins. Using the HIV-1 LTR as a tool to measure NF-κB activity, we identified that the HCV E1E2 glycoproteins and more so the E2 protein down-modulates HIV-1 LTR activation in 293T, TZM-bl and the more physiologically relevant Huh7 liver derived cell line. We demonstrate this effect is specifically mediated through inhibiting NF-κB binding to the LTR and show that this effect was conserved for all HCV genotypes tested. Transcriptomic analysis of 293T cells expressing the HCV glycoproteins identified E1E2 mediated stimulation of the endoplasmic reticulum (ER) stress response pathway and upregulation of stress response genes such as ATF3. Through shRNA mediated inhibition of ATF3, one of the components, we observed that E1E2 mediated inhibitory effects on HIV-1 LTR activity was alleviated. Our in vitro studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-κB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis.
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spelling pubmed-89649542022-03-31 The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway McKay, Lindsay G. A. Thomas, Jordan Albalawi, Wejdan Fattaccioli, Antoine Dieu, Marc Ruggiero, Alessandra McKeating, Jane A. Ball, Jonathan K. Tarr, Alexander W. Renard, Patricia Pollakis, Georgios Paxton, William A. Front Immunol Immunology Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be driven by host and viral genetic factors as well as HCV encoded immunomodulatory proteins. Using the HIV-1 LTR as a tool to measure NF-κB activity, we identified that the HCV E1E2 glycoproteins and more so the E2 protein down-modulates HIV-1 LTR activation in 293T, TZM-bl and the more physiologically relevant Huh7 liver derived cell line. We demonstrate this effect is specifically mediated through inhibiting NF-κB binding to the LTR and show that this effect was conserved for all HCV genotypes tested. Transcriptomic analysis of 293T cells expressing the HCV glycoproteins identified E1E2 mediated stimulation of the endoplasmic reticulum (ER) stress response pathway and upregulation of stress response genes such as ATF3. Through shRNA mediated inhibition of ATF3, one of the components, we observed that E1E2 mediated inhibitory effects on HIV-1 LTR activity was alleviated. Our in vitro studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-κB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis. Frontiers Media S.A. 2022-03-15 /pmc/articles/PMC8964954/ /pubmed/35371105 http://dx.doi.org/10.3389/fimmu.2022.831695 Text en Copyright © 2022 McKay, Thomas, Albalawi, Fattaccioli, Dieu, Ruggiero, McKeating, Ball, Tarr, Renard, Pollakis and Paxton 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
McKay, Lindsay G. A.
Thomas, Jordan
Albalawi, Wejdan
Fattaccioli, Antoine
Dieu, Marc
Ruggiero, Alessandra
McKeating, Jane A.
Ball, Jonathan K.
Tarr, Alexander W.
Renard, Patricia
Pollakis, Georgios
Paxton, William A.
The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title_full The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title_fullStr The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title_full_unstemmed The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title_short The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway
title_sort hcv envelope glycoprotein down-modulates nf-κb signalling and associates with stimulation of the host endoplasmic reticulum stress pathway
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964954/
https://www.ncbi.nlm.nih.gov/pubmed/35371105
http://dx.doi.org/10.3389/fimmu.2022.831695
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