Identification of DNA-Damage DNA-Binding Protein 1 as a Conditional Essential Factor for Cytomegalovirus Replication in Interferon-γ-Stimulated Cells

English version České info

The mouse cytomegaloviral (MCMV) protein pM27 represents an indispensable factor for viral fitness in vivo selectively, antagonizing signal transducer and activator of transcription 2 (STAT2)-mediated interferon signal transduction. We wished to explore by which molecular mechanism pM27 accomplishes this effect. We demonstrate that pM27 is essential and sufficient to curtail the protein half-life of STAT2 molecules. Pharmacologic inhibition of the proteasome restored STAT2 amounts, leading to poly-ubiquitin-conjugated STAT2 forms. PM27 was found in complexes with an essential host ubiquitin ligase complex adaptor protein, DNA-damage DNA-binding protein (DDB) 1. Truncation mutants of pM27 showed a strict correlation between DDB1 interaction and their ability to degrade STAT2. SiRNA-mediated knock-down of DDB1 restored STAT2 in the presence of pM27 and strongly impaired viral replication in interferon conditioned cells, thus phenocopying the growth attenuation of M27-deficient virus. In a constructive process, pM27 recruits DDB1 to exploit ubiquitin ligase complexes catalyzing the obstruction of the STAT2-dependent antiviral state of cells to permit viral replication.

Vyšlo v časopise: Identification of DNA-Damage DNA-Binding Protein 1 as a Conditional Essential Factor for Cytomegalovirus Replication in Interferon-γ-Stimulated Cells. PLoS Pathog 7(6): e32767. doi:10.1371/journal.ppat.1002069
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002069

Souhrn

Zdroje

1. LudwigAHengelH 2009 Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. Euro Surveill 14 26 32

2. MocarskiESShenkTPassRF 2007 Cytomegaloviruses. KnipeDKHowleyPM Field's Virology Philadelphia Lippincott, Williams & Wilkins 2701 2772

3. PolicBHengelHKrmpoticATrgovcichJPavicI 1998 Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188 1047 1054

4. CrozatKGeorgelPRutschmannSMannNDuX 2006 Analysis of the MCMV resistome by ENU mutagenesis. Mamm Genome 17 398 406

5. GilMPBohnEO'GuinAKRamanaCVLevineB 2001 Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A 98 6680 6685

6. PrestiRMPollockJLDal CantoAJO'GuinAKVirginHW 1998 Interferon gamma regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels. J Exp Med 188 577 588

7. PrestiRMPopkinDLConnickMPaetzoldSVirginHW 2001 Novel cell type-specific antiviral mechanism of interferon gamma action in macrophages. J Exp Med 193 483 496

8. StroblBBubicIBrunsUSteinbornRLajkoR 2005 Novel functions of tyrosine kinase 2 in the antiviral defense against murine cytomegalovirus. J Immunol 175 4000 4008

9. TabetaKGeorgelPJanssenEDuXHoebeK 2004 Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 101 3516 3521

10. HengelHKoszinowskiUHConzelmannKK 2005 Viruses know it all: new insights into IFN networks. Trends Immunol 26 396 401

11. ZimmermannATrillingMWagnerMWilbornMBubicI 2005 A cytomegaloviral protein reveals a dual role for STAT2 in IFN-{gamma} signaling and antiviral responses. J Exp Med 201 1543 1553

12. AbenesGLeeMHaghjooETongTZhanX 2001 Murine cytomegalovirus open reading frame M27 plays an important role in growth and virulence in mice. J Virol 75 1697 1707

13. KhanSZimmermannABaslerMGroettrupMHengelH 2004 A cytomegalovirus inhibitor of gamma interferon signaling controls immunoproteasome induction. J Virol 78 1831 1842

14. LeVTTrillingMZimmermannAHengelH 2008 Mouse cytomegalovirus inhibits beta interferon (IFN-beta) gene expression and controls activation pathways of the IFN-beta enhanceosome. J Gen Virol 89 1131 1141

15. ParkCLiSChaESchindlerC 2000 Immune response in Stat2 knockout mice. Immunity 13 795 804

16. HagaIRBowieAG 2005 Evasion of innate immunity by vaccinia virus. Parasitology 130 S11 S25

17. TrillingMLeVTZimmermannALudwigHPfefferK 2009 Gamma interferon-induced interferon regulatory factor 1-dependent antiviral response inhibits vaccinia virus replication in mouse but not human fibroblasts. J Virol 83 3684 3695

18. StancatoLFDavidMCarter-SuCLarnerACPrattWB 1996 Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. J Biol Chem 271 4134 4137

19. LeeCKBluyssenHALevyDE 1997 Regulation of interferon-alpha responsiveness by the duration of Janus kinase activity. J Biol Chem 272 21872 21877

20. KaspariMTavalaiNStammingerTZimmermannASchilfR 2008 Proteasome inhibitor MG132 blocks viral DNA replication and assembly of human cytomegalovirus. FEBS Lett 582 666 672

21. SatheshkumarPSAntonLCSanzPMossB 2009 Inhibition of the ubiquitin-proteasome system prevents vaccinia virus DNA replication and expression of intermediate and late genes. J Virol 83 2469 2479

22. AndrejevaJPooleEYoungDFGoodbournSRandallRE 2002 The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5. J Virol 76 11379 11386

23. PreciousBChildsKFitzpatrick-SwallowVGoodbournSRandallRE 2005 Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate the ubiquitination of STAT1. J Virol 79 13434 13441

24. UlaneCMHorvathCM 2002 Paramyxoviruses SV5 and HPIV2 assemble STAT protein ubiquitin ligase complexes from cellular components. Virology 304 160 166

25. UlaneCMRodriguezJJParisienJPHorvathCM 2003 STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling. J Virol 77 6385 6393

26. HuJMcCallCMOhtaTXiongY 2004 Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nat Cell Biol 6 1003 1009

27. LiuWNicholsAFGrahamJADualanRAbbasA 2000 Nuclear transport of human DDB protein induced by ultraviolet light. J Biol Chem 275 21429 21434

28. HwangBJToeringSFranckeUChuG 1998 p48 Activates a UV-damaged-DNA binding factor and is defective in xeroderma pigmentosum group E cells that lack binding activity. Mol Cell Biol 18 4391 4399

29. AngersSLiTYiXMacCossMJMoonRT 2006 Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443 590 593

30. JinJAriasEEChenJHarperJWWalterJC 2006 A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol Cell 23 709 721

31. NicholsAFItohTGrahamJALiuWYamaizumiM 2000 Human damage-specific DNA-binding protein p48. Characterization of XPE mutations and regulation following UV irradiation. J Biol Chem 275 21422 21428

32. LinGYPatersonRGRichardsonCDLambRA 1998 The V protein of the paramyxovirus SV5 interacts with damage-specific DNA binding protein. Virology 249 189 200

33. LiTChenXGarbuttKCZhouPZhengN 2006 Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase. Cell 124 105 117

34. LeVTTrillingMWilbornMHengelHZimmermannA 2008 Human cytomegalovirus interferes with signal transducer and activator of transcription (STAT) 2 protein stability and tyrosine phosphorylation. J Gen Virol 89 2416 2426

35. CangYZhangJNicholasSABastienJLiB 2006 Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Cell 127 929 940

36. WakasugiMMatsuuraKNagasawaAFuDShimizuH 2007 DDB1 gene disruption causes a severe growth defect and apoptosis in chicken DT40 cells. Biochem Biophys Res Commun 364 771 777

37. KarlasAMachuyNShinYPleissnerKPArtariniA 2010 Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463 818 822

38. KonigRZhouYEllederDDiamondTLBonamyGM 2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135 49 60

39. KonigRStertzSZhouYInoueAHoffmannHH 2010 Human host factors required for influenza virus replication. Nature 463 813 817

40. FukumotoYDohmaeNHanaokaF 2008 Schizosaccharomyces pombe Ddb1 recruits substrate-specific adaptor proteins through a novel protein motif, the DDB-box. Mol Cell Biol 28 6746 6756

41. ParisienJPLauJFHorvathCM 2002 STAT2 acts as a host range determinant for species-specific paramyxovirus interferon antagonism and simian virus 5 replication. J Virol 76 6435 6441

42. ParisienJPLauJFRodriguezJJUlaneCMHorvathCM 2002 Selective STAT protein degradation induced by paramyxoviruses requires both STAT1 and STAT2 but is independent of alpha/beta interferon signal transduction. J Virol 76 4190 4198

43. ChildsKSAndrejevaJRandallREGoodbournS 2009 Mechanism of mda-5 Inhibition by paramyxovirus V proteins. J Virol 83 1465 1473

44. PooleEHeBLambRARandallREGoodbournS 2002 The V proteins of simian virus 5 and other paramyxoviruses inhibit induction of interferon-beta. Virology 303 33 46

45. AndrejevaJYoungDFGoodbournSRandallRE 2002 Degradation of STAT1 and STAT2 by the V proteins of simian virus 5 and human parainfluenza virus type 2, respectively: consequences for virus replication in the presence of alpha/beta and gamma interferons. J Virol 76 2159 2167

46. WiebuschLNeuwirthAGrabenhenrichLVoigtSHagemeierC 2008 Cell cycle-independent expression of immediate-early gene 3 results in G1 and G2 arrest in murine cytomegalovirus-infected cells. J Virol 82 10188 10198

47. DurbinJEHackenmillerRSimonMCLevyDE 1996 Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84 443 450

48. BruneWHengelHKoszinowskiUH 2001 A mouse model for cytomegalovirus infection. Curr Protoc Immunol Chapter 19 Unit

49. NavarroLMowenKRodemsSWeaverBReichN 1998 Cytomegalovirus activates interferon immediate-early response gene expression and an interferon regulatory factor 3-containing interferon-stimulated response element-binding complex. Mol Cell Biol 18 3796 3802