The Downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 Axis and by Human Cytomegalovirus (HCMV) Associated Factors Allows the Activation of the HCMV Major IE Promoter and the Transition to Productive Infection

English version České info

Human cytomegalovirus (HCMV) is a significant pathogen that belongs to the herpesvirus family. Here we show that the histone H3K27 methyltransferase EZH2 and its regulators JARID2 and NDY1/KDM2B are required for the establishment of productive infection. Mechanistically, the EZH2-NDY1/KDM2B-JARID2 axis downregulates GFI1, a repressor of the HCMV major-immediate-early promoter (MIEP) and inhibition of this axis upregulates GFI1 and interferes with the activation of the MIEP and HCMV infection. GFI1 is rapidly downregulated during infection in both wild-type and EZH2, NDY1/KDM2B, JARID2 knockdown cells. However, since the starting levels of GFI1 in the latter are significantly higher, they remain high despite the virus-induced GFI1 downregulation, preventing the infection. Following the downregulation of GFI1 immediately after virus entry, HCMV initiates an EZH2-NDY1/KDM2B-JARID2-JMJD3-dependent program to maintain the low expression of GFI1 throughout the infection cycle. The knockdown of EZH2 also modulates the accumulation of histone H3K27me3 and H3K4me3 in the immediate-early region of HCMV, and by doing so, it may contribute directly to the MIEP repression induced by the knockdown of EZH2. These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program.

Vyšlo v časopise: The Downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 Axis and by Human Cytomegalovirus (HCMV) Associated Factors Allows the Activation of the HCMV Major IE Promoter and the Transition to Productive Infection. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004136
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004136

Souhrn

Zdroje

1. BoeckhM, GeballeAP (2011) Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 121 : 1673–1680.

2. SinzgerC, GrefteA, PlachterB, GouwAS, TheTH, et al. (1995) Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues. J Gen Virol 76 (Pt 4): 741–750.

3. SinclairJ (2008) Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol 41 : 180–185.

4. StreblowDN, NelsonJA (2003) Models of HCMV latency and reactivation. Trends Microbiol 11 : 293–295.

5. CastilloJP, KowalikTF (2002) Human cytomegalovirus immediate early proteins and cell growth control. Gene 290 : 19–34.

6. Zweidler-MckayPA, GrimesHL, FlubacherMM, TsichlisPN (1996) Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor. Mol Cell Biol 16 : 4024–4034.

7. GrimesHL, ChanTO, Zweidler-McKayPA, TongB, TsichlisPN (1996) The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal. Mol Cell Biol 16 : 6263–6272.

8. GilksCB, BearSE, GrimesHL, TsichlisPN (1993) Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein. Mol Cell Biol 13 : 1759–1768.

9. van der MeerLT, JansenJH, van der ReijdenBA (2010) Gfi1 and Gfi1b: key regulators of hematopoiesis. Leukemia 24 : 1834–1843.

10. PhelanJD, ShroyerNF, CookT, GebeleinB, GrimesHL (2010) Gfi1-cells and circuits: unraveling transcriptional networks of development and disease. Curr Opin Hematol 17 : 300–307.

11. Sharif-AskariE, VassenL, KosanC, KhandanpourC, GaudreauMC, et al. (2010) Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65. Mol Cell Biol 30 : 3929–3942.

12. SalequeS, KimJ, RookeHM, OrkinSH (2007) Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1. Mol Cell 27 : 562–572.

13. SinclairJH, BaillieJ, BryantLA, Taylor-WiedemanJA, SissonsJG (1992) Repression of human cytomegalovirus major immediate early gene expression in a monocytic cell line. J Gen Virol 73 (Pt 2): 433–435.

14. MurphyJC, FischleW, VerdinE, SinclairJH (2002) Control of cytomegalovirus lytic gene expression by histone acetylation. Embo J 21 : 1112–1120.

15. SinclairJ (2010) Chromatin structure regulates human cytomegalovirus gene expression during latency, reactivation and lytic infection. Biochim Biophys Acta 1799 : 286–295.

16. GrovesIJ, ReevesMB, SinclairJH (2009) Lytic infection of permissive cells with human cytomegalovirus is regulated by an intrinsic 'pre-immediate-early' repression of viral gene expression mediated by histone post-translational modification. J Gen Virol 90 : 2364–2374.

17. SaffertRT, KalejtaRF (2007) Human cytomegalovirus gene expression is silenced by Daxx-mediated intrinsic immune defense in model latent infections established in vitro. J Virol 81 : 9109–9120.

18. YeeLF, LinPL, StinskiMF (2007) Ectopic expression of HCMV IE72 and IE86 proteins is sufficient to induce early gene expression but not production of infectious virus in undifferentiated promonocytic THP-1 cells. Virology 363 : 174–188.

19. ReevesMB, LehnerPJ, SissonsJG, SinclairJH (2005) An in vitro model for the regulation of human cytomegalovirus latency and reactivation in dendritic cells by chromatin remodelling. J Gen Virol 86 : 2949–2954.

20. LusserA (2002) Acetylated, methylated, remodeled: chromatin states for gene regulation. Curr Opin Plant Biol 5 : 437–443.

21. IoudinkovaE, ArcangelettiMC, RynditchA, De ContoF, MottaF, et al. (2006) Control of human cytomegalovirus gene expression by differential histone modifications during lytic and latent infection of a monocytic cell line. Gene 384 : 120–128.

22. ReevesMB, SinclairJH (2010) Analysis of latent viral gene expression in natural and experimental latency models of human cytomegalovirus and its correlation with histone modifications at a latent promoter. J Gen Virol 91 : 599–604.

23. ReevesMB, MacAryPA, LehnerPJ, SissonsJG, SinclairJH (2005) Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci U S A 102 : 4140–4145.

24. NitzscheA, PaulusC, NevelsM (2008) Temporal dynamics of cytomegalovirus chromatin assembly in productively infected human cells. J Virol 82 : 11167–11180.

25. Cuevas-BennettC, ShenkT (2008) Dynamic histone H3 acetylation and methylation at human cytomegalovirus promoters during replication in fibroblasts. J Virol 82 : 9525–9536.

26. SuganumaT, WorkmanJL (2011) Signals and combinatorial functions of histone modifications. Annu Rev Biochem 80 : 473–499.

27. MullerJ, HartCM, FrancisNJ, VargasML, SenguptaA, et al. (2002) Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111 : 197–208.

28. KuzmichevA, NishiokaK, Erdjument-BromageH, TempstP, ReinbergD (2002) Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16 : 2893–2905.

29. HerzHM, ShilatifardA (2010) The JARID2-PRC2 duality. Genes Dev 24 : 857–861.

30. KottakisF, PolytarchouC, FoltopoulouP, SanidasI, KampranisSC, et al. (2011) FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell 43 : 285–298.

31. ShiY, LanF, MatsonC, MulliganP, WhetstineJR, et al. (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119 : 941–953.

32. KampranisSC, TsichlisPN (2009) Histone demethylases and cancer. Adv Cancer Res 102 : 103–169.

33. WenH, LiJ, SongT, LuM, KanPY, et al. (2010) Recognition of histone H3K4 trimethylation by the plant homeodomain of PHF2 modulates histone demethylation. J Biol Chem 285 : 9322–9326.

34. TzatsosA, PfauR, KampranisSC, TsichlisPN (2009) Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A 106 : 2641–2646.

35. SampaioKL, CavignacY, StierhofYD, SinzgerC (2005) Human cytomegalovirus labeled with green fluorescent protein for live analysis of intracellular particle movements. J Virol 79 : 2754–2767.

36. SnoeckR, AndreiG, NeytsJ, ScholsD, CoolsM, et al. (1993) Inhibitory activity of S-adenosylhomocysteine hydrolase inhibitors against human cytomegalovirus replication. Antiviral Res 21 : 197–216.

37. TanJ, YangX, ZhuangL, JiangX, ChenW, et al. (2007) Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 21 : 1050–1063.

38. De ClercqE (1990) Selective virus inhibitors. Microbiologica 13 : 165–178.

39. SchonrockN, BouveretR, LeroyO, BorghiL, KohlerC, et al. (2006) Polycomb-group proteins repress the floral activator AGL19 in the FLC-independent vernalization pathway. Genes Dev 20 : 1667–1678.

40. LiuS, CowellJK (2000) Cloning and characterization of the TATA-less promoter from the human GFI1 proto-oncogene. Ann Hum Genet 64 : 83–86.

41. DuanZ, ZarebskiA, Montoya-DurangoD, GrimesHL, HorwitzM (2005) Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol Cell Biol 25 : 10338–10351.

42. SalvantBS, FortunatoEA, SpectorDH (1998) Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription. J Virol 72 : 3729–3741.

43. FortunatoEA, SanchezV, YenJY, SpectorDH (2002) Infection of cells with human cytomegalovirus during S phase results in a blockade to immediate-early gene expression that can be overcome by inhibition of the proteasome. J Virol 76 : 5369–5379.

44. SaffertRT, KalejtaRF (2006) Inactivating a cellular intrinsic immune defense mediated by Daxx is the mechanism through which the human cytomegalovirus pp71 protein stimulates viral immediate-early gene expression. J Virol 80 : 3863–3871.

45. TavalaiN, PapiorP, RechterS, LeisM, StammingerT (2006) Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections. J Virol 80 : 8006–8018.

46. CantrellSR, BresnahanWA (2006) Human cytomegalovirus (HCMV) UL82 gene product (pp71) relieves hDaxx-mediated repression of HCMV replication. J Virol 80 : 6188–6191.

47. WoodhallDL, GrovesIJ, ReevesMB, WilkinsonG, SinclairJH (2006) Human Daxx-mediated repression of human cytomegalovirus gene expression correlates with a repressive chromatin structure around the major immediate early promoter. J Biol Chem 281 : 37652–37660.

48. TongB, GrimesHL, YangTY, BearSE, QinZ, et al. (1998) The Gfi-1B proto-oncoprotein represses p21WAF1 and inhibits myeloid cell differentiation. Mol Cell Biol 18 : 2462–2473.

49. AbrahamCG, KuleszaCA (2012) Polycomb repressive complex 2 targets murine cytomegalovirus chromatin for modification and associates with viral replication centers. PLoS One 7: e29410.

50. CaoR, WangH, HeJ, Erdjument-BromageH, TempstP, et al. (2008) Role of hPHF1 in H3K27 methylation and Hox gene silencing. Mol Cell Biol 28 : 1862–1872.

51. NekrasovM, KlymenkoT, FratermanS, PappB, OktabaK, et al. (2007) Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes. EMBO J 26 : 4078–4088.

52. White EA, Spector DH (2007) Early viral gene expression and function. In: Arvin A C-FG, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editor. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.

53. BresnahanWA, ShenkT (2000) A subset of viral transcripts packaged within human cytomegalovirus particles. Science 288 : 2373–2376.

54. GreijerAE, DekkersCA, MiddeldorpJM (2000) Human cytomegalovirus virions differentially incorporate viral and host cell RNA during the assembly process. J Virol 74 : 9078–9082.

55. SarcinellaE, BrownM, TellierR, PetricM, MazzulliT (2004) Detection of RNA in purified cytomegalovirus virions. Virus Res 104 : 129–137.

56. TerhuneSS, SchroerJ, ShenkT (2004) RNAs are packaged into human cytomegalovirus virions in proportion to their intracellular concentration. J Virol 78 : 10390–10398.

57. ProschS, PriemerC, HoflichC, LiebenthafC, BabelN, et al. (2003) Proteasome inhibitors: a novel tool to suppress human cytomegalovirus replication and virus-induced immune modulation. Antivir Ther 8 : 555–567.

58. TranK, MahrJA, SpectorDH (2010) Proteasome subunits relocalize during human cytomegalovirus infection, and proteasome activity is necessary for efficient viral gene transcription. J Virol 84 : 3079–3093.

59. BaldickCJJr, MarchiniA, PattersonCE, ShenkT (1997) Human cytomegalovirus tegument protein pp71 (ppUL82) enhances the infectivity of viral DNA and accelerates the infectious cycle. J Virol 71 : 4400–4408.

60. HofmannH, SindreH, StammingerT (2002) Functional interaction between the pp71 protein of human cytomegalovirus and the PML-interacting protein human Daxx. J Virol 76 : 5769–5783.

61. CantrellSR, BresnahanWA (2005) Interaction between the human cytomegalovirus UL82 gene product (pp71) and hDaxx regulates immediate-early gene expression and viral replication. J Virol 79 : 7792–7802.

62. HwangJ, KalejtaRF (2007) Proteasome-dependent, ubiquitin-independent degradation of Daxx by the viral pp71 protein in human cytomegalovirus-infected cells. Virology 367 : 334–338.

63. HwangJ, KalejtaRF (2009) Human cytomegalovirus protein pp71 induces Daxx SUMOylation. J Virol 83 : 6591–6598.

64. DoanLL, PorterSD, DuanZ, FlubacherMM, MontoyaD, et al. (2004) Targeted transcriptional repression of Gfi1 by GFI1 and GFI1B in lymphoid cells. Nucleic Acids Res 32 : 2508–2519.

65. DimitropoulouP, CaswellR, McSharryBP, GreavesRF, SpandidosDA, et al. (2010) Differential relocation and stability of PML-body components during productive human cytomegalovirus infection: detailed characterization by live-cell imaging. Eur J Cell Biol 89 : 757–768.

66. VanarsdallAL, WisnerTW, LeiH, KazlauskasA, JohnsonDC (2012) PDGF receptor-alpha does not promote HCMV entry into epithelial and endothelial cells but increased quantities stimulate entry by an abnormal pathway. PLoS Pathog 8: e1002905.

67. IgneaC, TrikkaFA, KourtzelisI, ArgiriouA, KanellisAK, et al. (2012) Positive genetic interactors of HMG2 identify a new set of genetic perturbations for improving sesquiterpene production in Saccharomyces cerevisiae. Microb Cell Fact 11 : 162.

68. PlachterB, BrittW, VornhagenR, StammingerT, JahnG (1993) Analysis of proteins encoded by IE regions 1 and 2 of human cytomegalovirus using monoclonal antibodies generated against recombinant antigens. Virology 193 : 642–652.

69. EverettRD, SourvinosG, OrrA (2003) Recruitment of herpes simplex virus type 1 transcriptional regulatory protein ICP4 into foci juxtaposed to ND10 in live, infected cells. J Virol 77 : 3680–3689.

70. PasiniD, HansenKH, ChristensenJ, AggerK, CloosPA, et al. (2008) Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and Polycomb-Repressive Complex 2. Genes Dev 22 : 1345–1355.

71. Montoya-DurangoDE, VeluCS, KazanjianA, RojasME, JayCM, et al. (2008) Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor. J Biol Chem 283 : 32056–32065.

72. AggerK, CloosPA, RudkjaerL, WilliamsK, AndersenG, et al. (2009) The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene -⁠ and stress-induced senescence. Genes Dev 23 : 1171–1176.

73. CarettiG, Di PadovaM, MicalesB, LyonsGE, SartorelliV (2004) The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev 18 : 2627–2638.

74. KloseRJ, YanQ, TothovaZ, YamaneK, Erdjument-BromageH, et al. (2007) The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128 : 889–900.