EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence

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Poxviruses are large dsDNA viruses that are renowned for regulating cellular pathways and manipulating the host immune response, including the NF-κB pathway. NF-κB inhibition by poxviruses is a growing area of interest and this family of viruses has developed multiple mechanisms to manipulate the pathway. Here, we focus on regulation of the NF-κB pathway by ectromelia virus, the causative agent of mousepox. We demonstrate that ectromelia virus is a potent inhibitor of the NF-κB pathway. Previously, we identified a family of four ectromelia virus genes that contain N-terminal ankyrin repeats and a C-terminal F-box domain that interacts with the cellular SCF ubiquitin ligase. Significantly, expression of the ankyrin/F-box protein, EVM005, inhibited NF-κB, and the F-box domain was critical for NF-κB inhibition and interaction with the SCF complex. Ectromelia virus devoid of EVM005 still inhibited NF-κB, indicating that multiple gene products contribute to NF-κB inhibition. Importantly, mice infected with ectromelia virus lacking EVM005 had a robust immune response, leading to viral clearance during infection. The data present two mechanisms, one in which EVM005 inhibits NF-κB activation through manipulation of the host SCF ubiquitin ligase complex, and an additional, NF-κB-independent mechanism that drives virulence.

Vyšlo v časopise: EVM005: An Ectromelia-Encoded Protein with Dual Roles in NF-κB Inhibition and Virulence. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004326
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004326

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Zdroje

1. HaydenMS, GhoshS (2008) Shared principles in NF-kappaB signaling. Cell 132: 344–362.

2. VallabhapurapuS, KarinM (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27: 693–733.

3. HiscottJ, KwonH, GeninP (2001) Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest 107: 143–151.

4. HiscottJ, NguyenTL, ArguelloM, NakhaeiP, PazS (2006) Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene 25: 6844–6867.

5. MohamedMR, McFaddenG (2009) NFkB inhibitors: strategies from poxviruses. Cell Cycle 8: 3125–3132.

6. Cahir McFarlandED, IzumiKM, MosialosG (1999) Epstein-barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-kappaB. Oncogene 18: 6959–6964.

7. RoulstonA, LinR, BeauparlantP, WainbergMA, HiscottJ (1995) Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors. Microbiol Rev 59: 481–505.

8. RamachandranA, HorvathCM (2009) Paramyxovirus disruption of interferon signal transduction: STATus report. J Interferon Cytokine Res 29: 531–537.

9. PowellPP, DixonLK, ParkhouseRM (1996) An IkappaB homolog encoded by African swine fever virus provides a novel mechanism for downregulation of proinflammatory cytokine responses in host macrophages. J Virol 70: 8527–8533.

10. Moss B (1996) Poxviridae: The Viruses and Their Replication. In: B.N. Fields DMK PMH, editor. Fields Virology. 3rd ed. Philadelphia, PA: Lippincott - Raven Publishers.

11. Fenner F (1996) Poxviruses. In: Fields B, Howley, PM, editor. Fields Virology. 3rd ed. Philadelphia, PA: Lippincott - Raven Publishers.

12. JohnstonJB, McFaddenG (2003) Poxvirus immunomodulatory strategies: current perspectives. J Virol 77: 6093–6100.

13. SeetBT, JohnstonJB, BrunettiCR, BarrettJW, EverettH, et al. (2003) Poxviruses and immune evasion. Annu Rev Immunol 21: 377–423.

14. SmithCA, DavisT, WignallJM, DinWS, FarrahT, et al. (1991) T2 open reading frame from the Shope fibroma virus encodes a soluble form of the TNF receptor. Biochem Biophys Res Commun 176: 335–342.

15. UptonC, MacenJL, SchreiberM, McFaddenG (1991) Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes to viral virulence. Virology 184: 370–382.

16. BowieA, Kiss-TothE, SymonsJA, SmithGL, DowerSK, et al. (2000) A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci U S A 97: 10162–10167.

17. StackJ, HagaIR, SchroderM, BartlettNW, MaloneyG, et al. (2005) Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med 201: 1007–1018.

18. SchroderM, BaranM, BowieAG (2008) Viral targeting of DEAD box protein 3 reveals its role in TBK1/IKKepsilon-mediated IRF activation. EMBO J 27: 2147–2157.

19. ChenRA, RyzhakovG, CoorayS, RandowF, SmithGL (2008) Inhibition of IkappaB kinase by vaccinia virus virulence factor B14. PLoS Pathog 4: e22.

20. DiPernaG, StackJ, BowieAG, BoydA, KotwalG, et al. (2004) Poxvirus protein N1L targets the I-kappaB kinase complex, inhibits signaling to NF-kappaB by the tumor necrosis factor superfamily of receptors, and inhibits NF-kappaB and IRF3 signaling by toll-like receptors. J Biol Chem 279: 36570–36578.

21. GedeyR, JinXL, HinthongO, ShislerJL (2006) Poxviral regulation of the host NF-kappaB response: the vaccinia virus M2L protein inhibits induction of NF-kappaB activation via an ERK2 pathway in virus-infected human embryonic kidney cells. J Virol 80: 8676–8685.

22. ShislerJL, JinXL (2004) The vaccinia virus K1L gene product inhibits host NF-kappaB activation by preventing IkappaBalpha degradation. J Virol 78: 3553–3560.

23. HinthongO, JinXL, ShislerJL (2008) Characterization of wild-type and mutant vaccinia virus M2L proteins' abilities to localize to the endoplasmic reticulum and to inhibit NF-kappaB activation during infection. Virology 373: 248–262.

24. MansurDS, Maluquer de MotesC, UnterholznerL, SumnerRP, FergusonBJ, et al. (2013) Poxvirus targeting of E3 ligase beta-TrCP by molecular mimicry: a mechanism to inhibit NF-kappaB activation and promote immune evasion and virulence. PLoS Pathog 9: e1003183.

25. van BuurenN, CouturierB, XiongY, BarryM (2008) Ectromelia virus encodes a novel family of F-box proteins that interact with the SCF complex. J Virol 82: 9917–9927.

26. MercerAA, FlemingSB, UedaN (2005) F-box-like domains are present in most poxvirus ankyrin repeat proteins. Virus Genes 31: 127–133.

27. KarinM, Ben-NeriahY (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18: 621–663.

28. TanakaK, KawakamiT, TateishiK, YashirodaH, ChibaT (2001) Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway. Biochimie 83: 351–356.

29. ChangSJ, HsiaoJC, SonnbergS, ChiangCT, YangMH, et al. (2009) Poxvirus host range protein CP77 contains an F-box-like domain that is necessary to suppress NF-kappaB activation by tumor necrosis factor alpha but is independent of its host range function. J Virol 83: 4140–4152.

30. JohnstonJB, WangG, BarrettJW, NazarianSH, ColwillK, et al. (2005) Myxoma virus M-T5 protects infected cells from the stress of cell cycle arrest through its interaction with host cell cullin-1. J Virol 79: 10750–10763.

31. MohamedMR, RahmanMM, LanchburyJS, ShattuckD, NeffC, et al. (2009) Proteomic screening of variola virus reveals a unique NF-kappaB inhibitor that is highly conserved among pathogenic orthopoxviruses. Proc Natl Acad Sci U S A 106: 9045–9050.

32. SonnbergS, FlemingSB, MercerAA (2009) A truncated two-alpha-helix F-box present in poxvirus ankyrin-repeat proteins is sufficient for binding the SCF1 ubiquitin ligase complex. J Gen Virol 90: 1224–1228.

33. SonnbergS, SeetBT, PawsonT, FlemingSB, MercerAA (2008) Poxvirus ankyrin repeat proteins are a unique class of F-box proteins that associate with cellular SCF1 ubiquitin ligase complexes. Proc Natl Acad Sci U S A 105: 10955–10960.

34. SperlingKM, SchwantesA, SchnierleBS, SutterG (2008) The highly conserved orthopoxvirus 68k ankyrin-like protein is part of a cellular SCF ubiquitin ligase complex. Virology 374: 234–239.

35. GammonDB, GowrishankarB, DuraffourS, AndreiG, UptonC, et al. (2010) Vaccinia virus-encoded ribonucleotide reductase subunits are differentially required for replication and pathogenesis. PLoS Pathog 6: e1000984.

36. RintoulJL, WangJ, GammonDB, van BuurenNJ, GarsonK, et al. (2011) A selectable and excisable marker system for the rapid creation of recombinant poxviruses. PLoS One 6: e24643.

37. GhoshS, MayMJ, KoppEB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16: 225–260.

38. HoffmannA, NatoliG, GhoshG (2006) Transcriptional regulation via the NF-kappaB signaling module. Oncogene 25: 6706–6716.

39. MohamedMR, RahmanMM, RiceA, MoyerRW, WerdenSJ, et al. (2009) Cowpox virus expresses a novel ankyrin repeat NF-kappaB inhibitor that controls inflammatory cell influx into virus-infected tissues and is critical for virus pathogenesis. J Virol 83: 9223–9236.

40. RubioD, XuRH, RemakusS, KrouseTE, TruckenmillerME, et al. (2013) Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection. Cell Host Microbe 13: 701–710.

41. WiltonBA, CampbellS, Van BuurenN, GarneauR, FurukawaM, et al. (2008) Ectromelia virus BTB/kelch proteins, EVM150 and EVM167, interact with cullin-3-based ubiquitin ligases. Virology 374: 82–99.

42. WangQ, BurlesK, CouturierB, RandallCM, ShislerJ, et al. (2014) Ectromelia Virus Encodes a BTB/kelch Protein, EVM150, That Inhibits NF-kappaB Signaling. J Virol 88: 4853–4865.

43. ChaudhriG, PanchanathanV, BullerRM, van den EertweghAJ, ClaassenE, et al. (2004) Polarized type 1 cytokine response and cell-mediated immunity determine genetic resistance to mousepox. Proc Natl Acad Sci U S A 101: 9057–9062.

44. EstebanDJ, BullerRM (2005) Ectromelia virus: the causative agent of mousepox. J Gen Virol 86: 2645–2659.

45. ParkerS, SiddiquiAM, OberleC, HembradorE, LanierR, et al. (2009) Mousepox in the C57BL/6 strain provides an improved model for evaluating anti-poxvirus therapies. Virology 385: 11–21.

46. RahmanMM, McFaddenG (2011) Modulation of NF-kappaB signalling by microbial pathogens. Nat Rev Microbiol 9: 291–306.

47. SuzukiH, ChibaT, KobayashiM, TakeuchiM, SuzukiT, et al. (1999) IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2. Biochem Biophys Res Commun 256: 127–132.

48. PerkusME, GoebelSJ, DavisSW, JohnsonGP, NortonEK, et al. (1991) Deletion of 55 open reading frames from the termini of vaccinia virus. Virology 180: 406–410.

49. WyattLS, EarlPL, EllerLA, MossB (2004) Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc Natl Acad Sci U S A 101: 4590–4595.

50. Fagan-GarciaK, BarryM (2011) A vaccinia virus deletion mutant reveals the presence of additional inhibitors of NF-kappaB. J Virol 85: 883–894.

51. OieKL, PickupDJ (2001) Cowpox virus and other members of the orthopoxvirus genus interfere with the regulation of NF-kappaB activation. Virology 288: 175–187.

52. WinstonJT, StrackP, Beer-RomeroP, ChuCY, ElledgeSJ, et al. (1999) The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 13: 270–283.

53. Besnard-GuerinC, BelaidouniN, LassotI, SegeralE, JobartA, et al. (2004) HIV-1 Vpu sequesters beta-transducin repeat-containing protein (betaTrCP) in the cytoplasm and provokes the accumulation of beta-catenin and other SCFbetaTrCP substrates. J Biol Chem 279: 788–795.

54. LangV, JanzenJ, FischerGZ, SonejiY, BeinkeS, et al. (2003) betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. Mol Cell Biol 23: 402–413.

55. HsiaoJC, ChaoCC, YoungMJ, ChangYT, ChoEC, et al. (2006) A poxvirus host range protein, CP77, binds to a cellular protein, HMG20A, and regulates its dissociation from the vaccinia virus genome in CHO-K1 cells. J Virol 80: 7714–7728.

56. HsiaoJC, ChungCS, DrillienR, ChangW (2004) The cowpox virus host range gene, CP77, affects phosphorylation of eIF2 alpha and vaccinia viral translation in apoptotic HeLa cells. Virology 329: 199–212.

57. FrescasD, PaganoM (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8: 438–449.

58. StuartD, GrahamK, SchreiberM, MacaulayC, McFaddenG (1991) The target DNA sequence for resolution of poxvirus replicative intermediates is an active late promoter. J Virol 65: 61–70.

59. MichelJJ, XiongY (1998) Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A. Cell Growth Differ 9: 435–449.

60. ParkerAK, ParkerS, YokoyamaWM, CorbettJA, BullerRM (2007) Induction of natural killer cell responses by ectromelia virus controls infection. J Virol 81: 4070–4079.

61. FleschIE, HollettNA, WongYC, TscharkeDC (2012) Linear fidelity in quantification of anti-viral CD8+ T cells. PLoS One 7: e39533.