Hepatitis C virus reveals a novel early control in acute immune response
| Autor: | Takaji Wakita, Jacques Hugon, Stéphanie Dabo, Fumiko Shinkai-Ouchi, Masayoshi Fukasawa, Daisuke Akazawa, Noëlla Arnaud, Eliane F. Meurs |
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| Přispěvatelé: | Hépacivirus et immunité innée, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Virology II, National Institute of Infectious Diseases [Tokyo], Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Meurs, Eliane, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Gastroenterology and hepatology
Receptors Retinoic Acid viruses Hepacivirus [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity eIF-2 Kinase 0302 clinical medicine Interferon RNA interference Molecular Cell Biology Biology (General) RNA Small Interfering 0303 health sciences Viral Immune Evasion virus diseases Antivirals Hepatitis C Innate Immunity Signaling Cascades 3. Good health Infectious hepatitis 030220 oncology & carcinogenesis Medicine Cytokines RNA Viral RNA Interference medicine.drug Research Article Signal Transduction TRIM25 QH301-705.5 Immunology Biology Microbiology Signaling Pathways Stress Signaling Cascade Cell Line 03 medical and health sciences Virology Genetics medicine Humans Kinase activity Molecular Biology Ubiquitins [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity Liver diseases 030304 developmental biology Adaptor Proteins Signal Transducing Innate immune system TNF Receptor-Associated Factor 3 Gene Expression Profiling Immunity Ubiquitination RC581-607 biochemical phenomena metabolism and nutrition ISG15 Protein kinase R Hepatocytes Parasitology Interferon Regulatory Factor-3 Interferons Immunologic diseases. Allergy IRF3 |
| Zdroj: | PLoS Pathogens PLoS Pathogens, 2011, 7 (10), pp.e1002289. ⟨10.1371/journal.ppat.1002289⟩ PLoS Pathogens, Public Library of Science, 2011, 7 (10), pp.e1002289. ⟨10.1371/journal.ppat.1002289⟩ PLoS Pathogens, Vol 7, Iss 10, p e1002289 (2011) |
| ISSN: | 1553-7366 1553-7374 |
| Popis: | 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. Author Summary Hepatitis C Virus (HCV) is a poor interferon (IFN) inducer, despite recognition of its RNA by the cytosolic RNA helicase RIG-I. This is due in part through cleavage of MAVS, a downstream adapter of RIG-I, by the HCV NS3/4A protease and through activation of the eIF2α-kinase PKR to control IFN translation. Here, we show that HCV also inhibits RIG-I activation through the ubiquitin-like protein ISG15 and that HCV triggers rapid induction of 49 genes, including ISG15, through a novel signaling pathway that precedes RIG-I and involves PKR as an adapter to recruit MAVS. Hence, we propose to divide the acute response to HCV infection into one early (PKR) and one late (RIG-I) phase, with the former controlling the latter. Furthermore, these data emphazise the need to check compounds designed as immune adjuvants for activation of the early acute phase before using them to sustain innate immunity. |
| Databáze: | OpenAIRE |
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