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

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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.

Vyšlo v časopise: Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002289
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002289

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1. GackMUShinYCJooCHUranoTLiangC 2007 TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446 916 920

2. GackMUKirchhoferAShinYCInnKSLiangC 2008 Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. Proc Natl Acad Sci U S A 105 16743 16748

3. YoneyamaMFujitaT 2009 RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev 227 54 65

4. BinderMKochsGBartenschlagerRLohmannV 2007 Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy. Hepatology 46 1365 1374

5. SaitoTOwenDMJiangFMarcotrigianoJGaleMJr 2008 Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454 523 527

6. SumpterRJrLooYMFoyELiKYoneyamaM 2005 Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79 2689 2699

7. MeylanECurranJHofmannKMoradpourDBinderM 2005 Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 1167 1172

8. ArnaudNDaboSMaillardPBudkowskaAKalliampakouKI 2010 Hepatitis C virus controls interferon production through PKR activation. PLoS One 5 e10575

9. GaraigortaUChisariFV 2009 Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation. Cell Host Microbe 6 513 522

10. MihmSFreseMMeierVWietzke-BraunPScharfJG 2004 Interferon type I gene expression in chronic hepatitis C. Lab Invest 84 1148 1159

11. Sarasin-FilipowiczMOakeleyEJDuongFHChristenVTerraccianoL 2008 Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 105 7034 7039

12. BiggerCBGuerraBBraskyKMHubbardGBeardMR 2004 Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees. J Virol 78 13779 13792

13. TakahashiKAsabeSWielandSGaraigortaUGastaminzaP 2010 Plasmacytoid dendritic cells sense hepatitis C virus-infected cells, produce interferon, and inhibit infection. Proc Natl Acad Sci U S A 107 7431 7436

14. AskariehGAlsioAPugnalePNegroFFerrariC 2010 Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepatology 51 1523 1530

15. AsselahTBiecheINarguetSSabbaghALaurendeauI 2008 Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 57 516 524

16. ChenLBorozanIFeldJSunJTannisLL 2005 Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 128 1437 1444

17. ChenLSunJMengLHeathcoteJEdwardsA 2010 ISG15, a ubiquitin-like interferon stimulated gene, promotes Hepatitis C Virus production in vitro: Implications for chronic infection and response to treatment. J Gen Virol 91 382 388

18. KimMJHwangSYImaizumiTYooJY 2008 Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol 82 1474 1483

19. AkazawaDDateTMorikawaKMurayamaAMiyamotoM 2007 CD81 expression is important for the permissiveness of Huh7 cell clones for heterogeneous hepatitis C virus infection. J Virol 81 5036 5045

20. NisoleSStoyeJPSaibA 2005 TRIM family proteins: retroviral restriction and antiviral defence. Nat Rev Microbiol 3 799 808

21. ZouWWangJZhangDE 2007 Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. Biochem Biophys Res Commun 354 321 327

22. JeonYJYooHMChungCH 2010 ISG15 and immune diseases. Biochim Biophys Acta 1802 485 496

23. KimKIYanMMalakhovaOLuoJKShenMF 2006 Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling. Mol Cell Biol 26 472 479

24. ChenWHBasuSBhattacharjeeAKCrossAS 2010 Enhanced antibody responses to a detoxified lipopolysaccharide-group B meningococcal outer membrane protein vaccine are due to synergistic engagement of Toll-like receptors. Innate Immun 16 322 332

25. BroeringRZhangXKottililSTripplerMJiangM 2010 The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response. Gut 59 1111 1119

26. ElcoCPGuentherJMWilliamsBRGSenGC 2005 Analysis of genes induced by Sendai virus infection of mutant cell lines reveals essential roles of interferon regulatory factor 3, NF-kappaB, and interferon but not toll-like receptor 3. J Virol 79 3920 3929

27. LooYMOwenDMLiKEricksonAKJohnsonCL 2006 Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A 103 6001 6006

28. BiggerCBBraskyKMLanfordRE 2001 DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J Virol 75 7059 7066

29. FarellPJBroezeRJLengyelP 1979 Accumulation of an mRNA and protein in interferon-treated Ehrlich ascites tumour cells. Nature (London) 279 523 524

30. HaasALAhrensPBrightPMAnkelH 1987 Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin. J Biol Chem 262 11315 11323

31. ZhaoCDenisonCHuibregtseJMGygiSKrugRM 2005 Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A 102 10200 10205

32. YuanWKrugRM 2001 Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. Embo J 20 362 371

33. WongJJPungYFSzeNSChinKC 2006 HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets. Proc Natl Acad Sci U S A 103 10735 10740

34. ZouWZhangDE 2006 The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase. J Biol Chem 281 3989 3994

35. DurfeeLALyonNSeoKHuibregtseJM 2010 The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15. Mol Cell 38 722 732

36. WielandSFChisariFV 2005 Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol 79 9369 9380

37. JiangJTangH 2010 Mechanism of inhibiting type I interferon induction by hepatitis B virus×protein. Prein Cell 1 1106 1117

38. WeiCNiCSongTLiuYYangX 2010 The hepatitis B virus×protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J Immunol 185 1158 1168

39. ChenGGLaiPBHoRLChanPKXuH 2004 Reduction of double-stranded RNA-activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus. J Med Virol 73 187 194

40. ShimoikeTMcKennaSALindhoutDAPuglisiJD 2009 Translational insensitivity to potent activation of PKR by HCV IRES RNA. Antiviral Res 83 228 237

41. NallagatlaSRHwangJToroneyRZhengXCameronCE 2007 5′-triphosphate-dependent activation of PKR by RNAs with short stem-loops. Science 318 1455 1458

42. GilJGarciaMAGomez-PuertasPGuerraSRullasJ 2004 TRAF family proteins link PKR with NF-kappa B activation. Mol Cell Biol 24 4502 4512

43. OganesyanGSahaSKGuoBHeJQShahangianA 2006 Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439 208 211

44. ZhangPSamuelCE 2008 Induction of protein kinase PKR-dependent activation of interferon regulatory factor 3 by vaccinia virus occurs through adapter IPS-1 signaling. J Biol Chem 283 34580 34587

45. McAllisterCSSamuelCE 2009 The RNA-activated protein kinase enhances the induction of interferon-beta and apoptosis mediated by cytoplasmic RNA sensors. J Biol Chem 284 1644 1651

46. McAllisterCSTothAMZhangPDevauxPCattaneoR 2010 Mechanisms of protein kinase PKR-mediated amplification of beta interferon induction by C protein-deficient measles virus. J Virol 84 380 386

47. StrahleLMarqJBBriniAHausmannSKolakofskyD 2007 Activation of the beta interferon promoter by unnatural Sendai virus infection requires RIG-I and is inhibited by viral C proteins. J Virol 81 12227 12237

48. Biron-AndreaniCRauletEPichard-GarciaLMaurelP 2010 Use of human hepatocytes to investigate blood coagulation factor. Methods Mol Biol 640 431 445

49. StrahleLGarcinDKolakofskyD 2006 Sendai virus defective-interfering genomes and the activation of interferon-beta. Virology 351 101 111

50. JammiNVWhitbyLRBealPA 2003 Small molecule inhibitors of the RNA-dependent protein kinase. Biochem Biophys Res Commun 308 50 57

51. NekhaiSBottaroDPWoldehawariatGSpellerbergAPetryshynR 2000 A cell-permeable peptide inhibits activation of PKR and enhances cell proliferation. Peptides 21 1449 1456

52. GrandvauxNServantMJtenOeverBSenGCBalachandranS 2002 Transcriptional profiling of interferon regulatory factor 3 target genes: direct involvement in the regulation of interferon-stimulated genes. J Virol 76 5532 5539

53. BonnetMCDauratCOttoneCMeursEF 2006 The N-terminus of PKR is responsible for the activation of the NF-kappaB signaling pathway by interacting with the IKK complex. Cell Signal 18 1865 1875

54. MalakhovMPKimKIMalakhovaOAJacobsBSBordenEC 2003 High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transduction. J Biol Chem 278 16608 16613

55. LaurentAGKrustBGalabruJSvabJHovanessianAG 1985 Monoclonal antibodies to interferon induced 68,000 Mr protein and their use for the detection of double-stranded RNA dependent protein kinase in human cells. Proc Natl Acad SciUSA 82 4341 4345

56. IwanoSIchikawaMTakizawaSHashimotoHMiyamotoY 2010 Identification of AhR-regulated genes involved in PAH-induced immunotoxicity using a highly-sensitive DNA chip, 3D-Gene Human Immunity and Metabolic Syndrome 9k. Toxicol In Vitro 24 85 91

57. WolffBSanglierJJWangY 1997 Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA. Chem Biol 4 139 147