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Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response

Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and t...

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Autores principales: Arnaud, Noëlla, Dabo, Stéphanie, Akazawa, Daisuke, Fukasawa, Masayoshi, Shinkai-Ouchi, Fumiko, Hugon, Jacques, Wakita, Takaji, Meurs, Eliane F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192838/
https://www.ncbi.nlm.nih.gov/pubmed/22022264
http://dx.doi.org/10.1371/journal.ppat.1002289
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author Arnaud, Noëlla
Dabo, Stéphanie
Akazawa, Daisuke
Fukasawa, Masayoshi
Shinkai-Ouchi, Fumiko
Hugon, Jacques
Wakita, Takaji
Meurs, Eliane F.
author_facet Arnaud, Noëlla
Dabo, Stéphanie
Akazawa, Daisuke
Fukasawa, Masayoshi
Shinkai-Ouchi, Fumiko
Hugon, Jacques
Wakita, Takaji
Meurs, Eliane F.
author_sort Arnaud, Noëlla
collection PubMed
description Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response.
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spelling pubmed-31928382011-10-21 Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response Arnaud, Noëlla Dabo, Stéphanie Akazawa, Daisuke Fukasawa, Masayoshi Shinkai-Ouchi, Fumiko Hugon, Jacques Wakita, Takaji Meurs, Eliane F. PLoS Pathog Research Article Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response. Public Library of Science 2011-10-13 /pmc/articles/PMC3192838/ /pubmed/22022264 http://dx.doi.org/10.1371/journal.ppat.1002289 Text en Arnaud et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Arnaud, Noëlla
Dabo, Stéphanie
Akazawa, Daisuke
Fukasawa, Masayoshi
Shinkai-Ouchi, Fumiko
Hugon, Jacques
Wakita, Takaji
Meurs, Eliane F.
Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title_full Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title_fullStr Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title_full_unstemmed Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title_short Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response
title_sort hepatitis c virus reveals a novel early control in acute immune response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192838/
https://www.ncbi.nlm.nih.gov/pubmed/22022264
http://dx.doi.org/10.1371/journal.ppat.1002289
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