Human Cytomegalovirus pUL79 Is an Elongation Factor of RNA Polymerase II for Viral Gene Transcription
In this study, we report a novel mechanism used by human cytomegalovirus (HCMV) to regulate the elongation rate of RNA polymerase II (RNAP II) to facilitate viral transcription during late stages of infection. Recently, we and others have identified several viral factors that regulate gene expression during late infection. These factors are functionally conserved among beta- and gamma- herpesviruses, suggesting a unique transcriptional regulation shared by viruses of these two subfamilies. However, the mechanism remains elusive. Here we show that HCMV pUL79, one of these factors, interacts with RNAP II as well as other viral factors involved in late gene expression. We have started to elucidate the nature of the pUL79-RNAP II interaction, finding that pUL79 does not alter the protein levels of RNAP II or its recruitment to viral promoters. However, during late times of infection, pUL79 helps RNAP II efficiently elongate along the viral DNA template to transcribe HCMV genes. Host genes are not regulated by this pUL79-mediated mechanism. Therefore, our study discovers a previously uncharacterized mechanism where RNAP II activity is modulated by viral factor pUL79, and potentially other viral factors as well, for coordinated viral transcription.
Vyšlo v časopise:
Human Cytomegalovirus pUL79 Is an Elongation Factor of RNA Polymerase II for Viral Gene Transcription. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004350
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004350
Souhrn
In this study, we report a novel mechanism used by human cytomegalovirus (HCMV) to regulate the elongation rate of RNA polymerase II (RNAP II) to facilitate viral transcription during late stages of infection. Recently, we and others have identified several viral factors that regulate gene expression during late infection. These factors are functionally conserved among beta- and gamma- herpesviruses, suggesting a unique transcriptional regulation shared by viruses of these two subfamilies. However, the mechanism remains elusive. Here we show that HCMV pUL79, one of these factors, interacts with RNAP II as well as other viral factors involved in late gene expression. We have started to elucidate the nature of the pUL79-RNAP II interaction, finding that pUL79 does not alter the protein levels of RNAP II or its recruitment to viral promoters. However, during late times of infection, pUL79 helps RNAP II efficiently elongate along the viral DNA template to transcribe HCMV genes. Host genes are not regulated by this pUL79-mediated mechanism. Therefore, our study discovers a previously uncharacterized mechanism where RNAP II activity is modulated by viral factor pUL79, and potentially other viral factors as well, for coordinated viral transcription.
Zdroje
1. CroughT, KhannaR (2009) Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev 22: 76–98.
2. DeaytonJR, Prof SabinCA, JohnsonMA, EmeryVC, WilsonP, et al. (2004) Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 363: 2116–2121.
3. BuonsensoD, SerrantiD, GargiulloL, CeccarelliM, RannoO, et al. (2012) Congenital cytomegalovirus infection: current strategies and future perspectives. Eur Rev Med Pharmacol Sci 16: 919–935.
4. GrattanMT, Moreno-CabralCE, StarnesVA, OyerPE, StinsonEB, et al. (1989) Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. Jama 261: 3561–3566.
5. KuvinJT, KimmelstielCD (1999) Infectious causes of atherosclerosis. Am Heart J 137: 216–226.
6. MelnickJL, AdamE, DebakeyME (1993) Cytomegalovirus and atherosclerosis. Eur Heart J 14 Suppl K: 30–38.
7. MuhlesteinJB, HorneBD, CarlquistJF, MadsenTE, BairTL, et al. (2000) Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. Circulation 102: 1917–1923.
8. SpeirE, ModaliR, HuangES, LeonMB, ShawlF, et al. (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265: 391–394.
9. StreblowDN, OrloffSL, NelsonJA (2001) Do pathogens accelerate atherosclerosis? J Nutr 131: 2798S–2804S.
10. ZhouYF, LeonMB, WaclawiwMA, PopmaJJ, YuZX, et al. (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335: 624–630.
11. RanganathanP, ClarkPA, KuoJS, SalamatMS, KalejtaRF (2012) Significant association of multiple human cytomegalovirus genomic Loci with glioblastoma multiforme samples. J Virol 86: 854–864.
12. DziurzynskiK, ChangSM, HeimbergerAB, KalejtaRF, McGregor DallasSR, et al. (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14: 246–255.
13. JohnsenJI, BaryawnoN, Soderberg-NauclerC (2011) Is human cytomegalovirus a target in cancer therapy? Oncotarget 2: 1329–1338.
14. BaryawnoN, RahbarA, Wolmer-SolbergN, TaherC, OdebergJ, et al. (2011) Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest 121: 4043–4055.
15. Anders DG, Kerry JA, Pari GS (2007) DNA synthesis and late viral gene expression. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, et al.., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.
16. Stinski MF, Meier JL (2007) Immediate-early viral gene regulation and function. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, et al.., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.
17. White EA, Spector DH (2007) Early viral gene expression and function. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, et al.., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.
18. Mocarski Jr E (2007) Betaherpes viral genes and their functions. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, et al.., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.
19. GawnJM, GreavesRF (2002) Absence of IE1 p72 protein function during low-multiplicity infection by human cytomegalovirus results in a broad block to viral delayed-early gene expression. J Virol 76: 4441–4455.
20. GreavesRF, MocarskiES (1998) Defective growth correlates with reduced accumulation of a viral DNA replication protein after low-multiplicity infection by a human cytomegalovirus ie1 mutant. J Virol 72: 366–379.
21. StinskiMF, PetrikDT (2008) Functional roles of the human cytomegalovirus essential IE86 protein. Curr Top Microbiol Immunol 325: 133–152.
22. StinskiMF (1978) Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides. J Virol 26: 686–701.
23. AmonW, BinneUK, BryantH, JenkinsPJ, KarsteglCE, et al. (2004) Lytic cycle gene regulation of Epstein-Barr virus. J Virol 78: 13460–13469.
24. MohrH, MohrCA, SchneiderMR, ScrivanoL, AdlerB, et al. (2012) Cytomegalovirus replicon-based regulation of gene expression in vitro and in vivo. PLoS Pathog 8: e1002728.
25. DengH, ChuJT, ParkNH, SunR (2004) Identification of cis sequences required for lytic DNA replication and packaging of murine gammaherpesvirus 68. J Virol 78: 9123–9131.
26. WileySR, KrausRJ, ZuoF, MurrayEE, LoritzK, et al. (1993) SV40 early-to-late switch involves titration of cellular transcriptional repressors. Genes Dev 7: 2206–2219.
27. ZuoF, MertzJE (1995) Simian virus 40 late gene expression is regulated by members of the steroid/thyroid hormone receptor superfamily. Proc Natl Acad Sci U S A 92: 8586–8590.
28. KellerJM, AlwineJC (1984) Activation of the SV40 late promoter: direct effects of T antigen in the absence of viral DNA replication. Cell 36: 381–389.
29. BradyJ, BolenJB, RadonovichM, SalzmanN, KhouryG (1984) Stimulation of simian virus 40 late gene expression by simian virus 40 tumor antigen. Proc Natl Acad Sci U S A 81: 2040–2044.
30. JiaR, LiuX, TaoM, KruhlakM, GuoM, et al. (2009) Control of the papillomavirus early-to-late switch by differentially expressed SRp20. J Virol 83: 167–180.
31. FarleyDC, BrownJL, LeppardKN (2004) Activation of the early-late switch in adenovirus type 5 major late transcription unit expression by L4 gene products. J Virol 78: 1782–1791.
32. MorrisSJ, ScottGE, LeppardKN (2010) Adenovirus late-phase infection is controlled by a novel L4 promoter. J Virol 84: 7096–7104.
33. IftodeC, FlintSJ (2004) Viral DNA synthesis-dependent titration of a cellular repressor activates transcription of the human adenovirus type 2 IVa2 gene. Proc Natl Acad Sci U S A 101: 17831–17836.
34. JohnsonPA, EverettRD (1986) The control of herpes simplex virus type-1 late gene transcription: a ‘TATA-box’/cap site region is sufficient for fully efficient regulated activity. Nucleic Acids Res 14: 8247–8264.
35. Mavromara-NazosP, RoizmanB (1987) Activation of herpes simplex virus 1 gamma 2 genes by viral DNA replication. Virology 161: 593–598.
36. CarrozzaMJ, DeLucaNA (1996) Interaction of the viral activator protein ICP4 with TFIID through TAF250. Mol Cell Biol 16: 3085–3093.
37. ZhouC, KnipeDM (2002) Association of Herpes Simplex Virus Type 1 ICP8 and ICP27 Proteins with Cellular RNA Polymerase II Holoenzyme. J Virol 76: 5893–5904.
38. RiceSA, KnipeDM (1990) Genetic evidence for two distinct transactivation functions of the herpes simplex virus alpha protein ICP27. J Virol 64: 1704–1715.
39. GaoM, KnipeDM (1991) Potential role for herpes simplex virus ICP8 DNA replication protein in stimulation of late gene expression. J Virol 65: 2666–2675.
40. KimDB, ZabierowskiS, DeLucaNA (2002) The initiator element in a herpes simplex virus type 1 late-gene promoter enhances activation by ICP4, resulting in abundant late-gene expression. J Virol 76: 1548–1558.
41. OmotoS, MocarskiES (2013) Cytomegalovirus UL91 is essential for transcription of viral true late (gamma2) genes. J Virol 87: 8651–8664.
42. PerngYC, QianZ, FehrAR, XuanB, YuD (2011) The human cytomegalovirus gene UL79 is required for the accumulation of late viral transcripts. J Virol 85: 4841–4852.
43. IsomuraH, StinskiMF, MurataT, YamashitaY, KandaT, et al. (2011) The Human Cytomegalovirus Gene Products Essential for Late Viral Gene Expression Assemble into Prereplication Complexes before Viral DNA Replication. J Virol 85: 6629–6644.
44. ChapaTJ, JohnsonLS, AffolterC, ValentineMC, FehrAR, et al. (2013) Murine cytomegalovirus protein pM79 is a key regulator for viral late transcription. J Virol 87: 9135–9147.
45. ChapaTJ, PerngYC, FrenchAR, YuD (2014) Murine Cytomegalovirus Protein pM92 Is a Conserved Regulator of Viral Late Gene Expression. J Virol 88: 131–142.
46. ArumugaswamiV, WuTT, Martinez-GuzmanD, JiaQ, DengH, et al. (2006) ORF18 is a transfactor that is essential for late gene transcription of a gammaherpesvirus. J Virol 80: 9730–9740.
47. WongE, WuTT, ReyesN, DengH, SunR (2007) Murine gammaherpesvirus 68 open reading frame 24 is required for late gene expression after DNA replication. J Virol 81: 6761–6764.
48. WuTT, ParkT, KimH, TranT, TongL, et al. (2009) ORF30 and ORF34 are essential for expression of late genes in murine gammaherpesvirus 68. J Virol 83: 2265–2273.
49. JiaQ, WuTT, LiaoHI, ChernishofV, SunR (2004) Murine gammaherpesvirus 68 open reading frame 31 is required for viral replication. J Virol 78: 6610–6620.
50. GruffatH, KadjoufF, MariameB, ManetE (2012) The Epstein-Barr virus BcRF1 gene product is a TBP-like protein with an essential role in late gene expression. J Virol 86: 6023–6032.
51. WyrwiczLS, RychlewskiL (2007) Identification of Herpes TATT-binding protein. Antiviral Res 75: 167–172.
52. ChapmanRD, HeidemannM, HintermairC, EickD (2008) Molecular evolution of the RNA polymerase II CTD. Trends Genet 24: 289–296.
53. PeralesR, BentleyD (2009) “Cotranscriptionality”: the transcription elongation complex as a nexus for nuclear transactions. Mol Cell 36: 178–191.
54. SmithE, ShilatifardA (2010) The chromatin signaling pathway: diverse mechanisms of recruitment of histone-modifying enzymes and varied biological outcomes. Mol Cell 40: 689–701.
55. MayerA, LidschreiberM, SiebertM, LeikeK, SodingJ, et al. (2010) Uniform transitions of the general RNA polymerase II transcription complex. Nat Struct Mol Biol 17: 1272–1278.
56. BatailleAR, JeronimoC, JacquesPE, LarameeL, FortinME, et al. (2012) A universal RNA polymerase II CTD cycle is orchestrated by complex interplays between kinase, phosphatase, and isomerase enzymes along genes. Mol Cell 45: 158–170.
57. LuH, FloresO, WeinmannR, ReinbergD (1991) The nonphosphorylated form of RNA polymerase II preferentially associates with the preinitiation complex. Proc Natl Acad Sci U S A 88: 10004–10008.
58. SogaardTM, SvejstrupJQ (2007) Hyperphosphorylation of the C-terminal repeat domain of RNA polymerase II facilitates dissociation of its complex with mediator. J Biol Chem 282: 14113–14120.
59. MarshallNF, PengJ, XieZ, PriceDH (1996) Control of RNA polymerase II elongation potential by a novel carboxyl-terminal domain kinase. J Biol Chem 271: 27176–27183.
60. ChoH, KimTK, ManceboH, LaneWS, FloresO, et al. (1999) A protein phosphatase functions to recycle RNA polymerase II. Genes Dev 13: 1540–1552.
61. KrishnamurthyS, HeX, Reyes-ReyesM, MooreC, HampseyM (2004) Ssu72 Is an RNA polymerase II CTD phosphatase. Mol Cell 14: 387–394.
62. TamrakarS, KapasiAJ, SpectorDH (2005) Human cytomegalovirus infection induces specific hyperphosphorylation of the carboxyl-terminal domain of the large subunit of RNA polymerase II that is associated with changes in the abundance, activity, and localization of cdk9 and cdk7. J Virol 79: 15477–15493.
63. 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.
64. SanchezV, McElroyAK, YenJ, TamrakarS, ClarkCL, et al. (2004) Cyclin-Dependent Kinase Activity Is Required at Early Times for Accurate Processing and Accumulation of the Human Cytomegalovirus UL122–123 and UL37 Immediate-Early Transcripts and at Later Times for Virus Production. J Virol 78: 11219–11232.
65. NuccitelliR, TranK, SheikhS, AthosB, KreisM, et al. Optimized nanosecond pulsed electric field therapy can cause murine malignant melanomas to self-destruct with a single treatment. Int J Cancer 127: 1727–1736.
66. KageleD, RossettoCC, TarrantMT, PariGS (2012) Analysis of the interactions of viral and cellular factors with human cytomegalovirus lytic origin of replication, oriLyt. Virology 424: 106–114.
67. StrangBL, SinigaliaE, SilvaLA, CoenDM, LoregianA (2009) Analysis of the association of the human cytomegalovirus DNA polymerase subunit UL44 with the viral DNA replication factor UL84. J Virol 83: 7581–7589.
68. WangL, LiM, CaiM, XingJ, WangS, et al. (2012) A PY-nuclear localization signal is required for nuclear accumulation of HCMV UL79 protein. Med Microbiol Immunol 201: 381–387.
69. BaekMC, KroskyPM, PearsonA, CoenDM (2004) Phosphorylation of the RNA polymerase II carboxyl-terminal domain in human cytomegalovirus-infected cells and in vitro by the viral UL97 protein kinase. Virology 324: 184–193.
70. SmaleST (2009) Nuclear run-on assay. Cold Spring Harb Protoc 2009: pdb prot5329.
71. MaiuriP, KnezevichA, De MarcoA, MazzaD, KulaA, et al. (2011) Fast transcription rates of RNA polymerase II in human cells. EMBO Rep 12: 1280–1285.
72. NitzscheA, SteinhausserC, MuckeK, PaulusC, NevelsM (2012) Histone h3 lysine 4 methylation marks postreplicative human cytomegalovirus chromatin. J Virol 86: 9817–9827.
73. ChangKC, HansenE, ForoniL, LidaJ, GoldspinkG (1991) Molecular and functional analysis of the virus- and interferon-inducible human MxA promoter. Arch Virol 117: 1–15.
74. KnoblachT, GrandelB, SeilerJ, NevelsM, PaulusC (2011) Human cytomegalovirus IE1 protein elicits a type II interferon-like host cell response that depends on activated STAT1 but not interferon-gamma. PLoS Pathogens 7: e1002016.
75. HwangJ, SaffertRT, KalejtaRF (2011) Elongin B-mediated epigenetic alteration of viral chromatin correlates with efficient human cytomegalovirus gene expression and replication. MBio 2: e00023-00011.
76. MbonyeU, KarnJ (2014) Transcriptional control of HIV latency: Cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology 454-455C: 328–339.
77. FonsecaGJ, CohenMJ, MymrykJS (2014) Adenovirus E1A Recruits the Human Paf1 Complex To Enhance Transcriptional Elongation. J Virol 88: 5630–5637.
78. Dai-JuJQ, LiL, JohnsonLA, Sandri-GoldinRM (2006) ICP27 interacts with the C-terminal domain of RNA polymerase II and facilitates its recruitment to herpes simplex virus 1 transcription sites, where it undergoes proteasomal degradation during infection. J Virol 80: 3567–3581.
79. OuM, Sandri-GoldinRM (2013) Inhibition of cdk9 during herpes simplex virus 1 infection impedes viral transcription. PLoS ONE 8: e79007.
80. DurandLO, RoizmanB (2008) Role of cdk9 in the optimization of expression of the genes regulated by ICP22 of herpes simplex virus 1. J Virol 82: 10591–10599.
81. FraserKA, RiceSA (2007) Herpes simplex virus immediate-early protein ICP22 triggers loss of serine 2-phosphorylated RNA polymerase II. J Virol 81: 5091–5101.
82. BuratowskiS (1994) The basics of basal transcription by RNA polymerase II. Cell 77: 1–3.
83. AhnSH, KeoghMC, BuratowskiS (2009) Ctk1 promotes dissociation of basal transcription factors from elongating RNA polymerase II. EMBO J 28: 205–212.
84. YudkovskyN, RanishJA, HahnS (2000) A transcription reinitiation intermediate that is stabilized by activator. Nature 408: 225–229.
85. NitzscheA, PaulusC, NevelsM (2008) Temporal dynamics of cytomegalovirus chromatin assembly in productively infected human cells. J Virol 82: 11167–11180.
86. WingBA, JohnsonRA, HuangES (1998) Identification of positive and negative regulatory regions involved in regulating expression of the human cytomegalovirus UL94 late promoter: role of IE2-86 and cellular p53 in mediating negative regulatory function. J Virol 72: 1814–1825.
87. McWattersBJ, StenbergRM, KerryJA (2002) Characterization of the human cytomegalovirus UL75 (glycoprotein H) late gene promoter. Virology 303: 309–316.
88. LeachFS, MocarskiES (1989) Regulation of cytomegalovirus late-gene expression: differential use of three start sites in the transcriptional activation of ICP36 gene expression. J Virol 63: 1783–1791.
89. GathererD, SeirafianS, CunninghamC, HoltonM, DarganDJ, et al. (2011) High-resolution human cytomegalovirus transcriptome. Proc Natl Acad Sci U S A 108: 19755–19760.
90. KerryJA, PriddyMA, KohlerCP, StaleyTL, WeberD, et al. (1997) Translational regulation of the human cytomegalovirus pp28 (UL99) late gene. J Virol 71: 981–987.
91. JahnG, KouzaridesT, MachM, SchollBC, PlachterB, et al. (1987) Map position and nucleotide sequence of the gene for the large structural phosphoprotein of human cytomegalovirus. J Virol 61: 1358–1367.
92. EverettRD, ParsyML, OrrA (2009) Analysis of the functions of herpes simplex virus type 1 regulatory protein ICP0 that are critical for lytic infection and derepression of quiescent viral genomes. J Virol 83: 4963–4977.
93. WarmingS, CostantinoN, CourtDL, JenkinsNA, CopelandNG (2005) Simple and highly efficient BAC recombineering using galK selection. Nucleic Acids Res 33: e36.
94. ParedesAM, YuD (2012) Human cytomegalovirus: bacterial artificial chromosome (BAC) cloning and genetic manipulation. Curr Protoc Microbiol Chapter 14: Unit14E 14.
95. TerhuneS, TorigoiE, MoormanN, SilvaM, QianZ, et al. (2007) Human cytomegalovirus UL38 protein blocks apoptosis. J Virol 81: 3109–3123.
96. YuD, SmithGA, EnquistLW, ShenkT (2002) Construction of a self-excisable bacterial artificial chromosome containing the human cytomegalovirus genome and mutagenesis of the diploid TRL/IRL13 gene. J Virol 76: 2316–2328.
97. SilvaLA, StrangBL, LinEW, KamilJP, CoenDM (2011) Sites and roles of phosphorylation of the human cytomegalovirus DNA polymerase subunit UL44. Virology 417: 268–280.
98. StrangBL, BoulantS, CoenDM (2010) Nucleolin associates with the human cytomegalovirus DNA polymerase accessory subunit UL44 and is necessary for efficient viral replication. J Virol 84: 1771–1784.
99. DonnerAJ, EbmeierCC, TaatjesDJ, EspinosaJM (2010) CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol 17: 194–201.
100. PatroneG, PuppoF, CusanoR, ScaranariM, CeccheriniI, et al. (2000) Nuclear run-on assay using biotin labeling, magnetic bead capture and analysis by fluorescence-based RT-PCR. Biotechniques 29: 1012–1017, 1012-1014, 1016-1017.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2014 Číslo 8
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Disruption of Fas-Fas Ligand Signaling, Apoptosis, and Innate Immunity by Bacterial Pathogens
- Ly6C Monocyte Recruitment Is Responsible for Th2 Associated Host-Protective Macrophage Accumulation in Liver Inflammation due to Schistosomiasis
- Host Responses to Group A Streptococcus: Cell Death and Inflammation
- Pathogenicity and Epithelial Immunity