#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

A Locus Encompassing the Epstein-Barr Virus Kinase Regulates Expression of Genes Encoding Viral Structural Proteins


Epstein-Barr virus (EBV) is linked to the development of several types of cancer. Synthesis of structural proteins, a group of proteins that forms the protein shell around the viral genome, is essential for EBV infection and pathogenesis. Genes encoding structural proteins are expressed late in the viral life cycle after amplification of the viral genome. The mechanism controlling expression of this group of proteins represents a longstanding conundrum in EBV and other DNA viruses. In this report, we demonstrate that two EBV regulatory proteins control synthesis of mRNAs encoding viral structural proteins. These two proteins are: BGLF4, a protein kinase conserved in all herpesviruses, and BGLF3, a protein of unknown function with no cellular counterparts. We present evidence that the enzymatic activity of BGLF4 is required after replication of viral DNA to stimulate expression of structural proteins. BGLF3 and BGLF4 are expressed from the same locus in the genome; the two proteins work in concert and independently to promote expression of viral genes encoding structural proteins. Our findings provide novel insights into control of expression of genes encoding viral structural proteins. The enzymatic activity of BGLF4 is a potential target for development of new antiviral drugs.


Vyšlo v časopise: A Locus Encompassing the Epstein-Barr Virus Kinase Regulates Expression of Genes Encoding Viral Structural Proteins. PLoS Pathog 10(8): e32767. doi:10.1371/journal.ppat.1004307
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004307

Souhrn

Epstein-Barr virus (EBV) is linked to the development of several types of cancer. Synthesis of structural proteins, a group of proteins that forms the protein shell around the viral genome, is essential for EBV infection and pathogenesis. Genes encoding structural proteins are expressed late in the viral life cycle after amplification of the viral genome. The mechanism controlling expression of this group of proteins represents a longstanding conundrum in EBV and other DNA viruses. In this report, we demonstrate that two EBV regulatory proteins control synthesis of mRNAs encoding viral structural proteins. These two proteins are: BGLF4, a protein kinase conserved in all herpesviruses, and BGLF3, a protein of unknown function with no cellular counterparts. We present evidence that the enzymatic activity of BGLF4 is required after replication of viral DNA to stimulate expression of structural proteins. BGLF3 and BGLF4 are expressed from the same locus in the genome; the two proteins work in concert and independently to promote expression of viral genes encoding structural proteins. Our findings provide novel insights into control of expression of genes encoding viral structural proteins. The enzymatic activity of BGLF4 is a potential target for development of new antiviral drugs.


Zdroje

1. SongMJ, HwangS, WongWH, WuTT, LeeS, et al. (2005) Identification of viral genes essential for replication of murine gamma-herpesvirus 68 using signature-tagged mutagenesis. Proceedings of the National Academy of Sciences of the United States of America 102: 3805–3810.

2. 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.

3. 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.

4. 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.

5. PerngYC, QianZ, FehrAR, XuanB, YuD (2011) The human cytomegalovirus gene UL79 is required for the accumulation of late viral transcripts. Journal of virology 85: 4841–4852.

6. 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. Journal of virology 85: 6629–6644.

7. WyrwiczLS, RychlewskiL (2007) Identification of Herpes TATT-binding protein. Antiviral research 75: 167–172.

8. 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. Journal of virology 86: 6023–6032.

9. SerioTR, CahillN, ProutME, MillerG (1998) A functionally distinct TATA box required for late progression through the Epstein-Barr virus life cycle. Journal of Virology 72: 8338–8343.

10. IsomuraH, StinskiMF, KudohA, MurataT, NakayamaS, et al. (2008) Noncanonical TATA sequence in the UL44 late promoter of human cytomegalovirus is required for the accumulation of late viral transcripts. Journal of virology 82: 1638–1646.

11. TangS, YamanegiK, ZhengZM (2004) Requirement of a 12-base-pair TATT-containing sequence and viral lytic DNA replication in activation of the Kaposi's sarcoma-associated herpesvirus K8.1 late promoter. J Virol 78: 2609–2614.

12. HeilmannAM, CalderwoodMA, PortalD, LuY, JohannsenE (2012) Genome-wide analysis of epstein-barr virus rta DNA binding. Journal of virology 86: 5151–5164.

13. ChuaHH, LeeHH, ChangSS, LuCC, YehTH, et al. (2007) Role of the TSG101 gene in Epstein-Barr virus late gene transcription. J Virol 81: 2459–2471.

14. 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.

15. DeMerittIB, PodduturiJP, TilleyAM, NogalskiMT, YurochkoAD (2006) Prolonged activation of NF-kappaB by human cytomegalovirus promotes efficient viral replication and late gene expression. Virology 346: 15–31.

16. ChenMR, ChangSJ, HuangH, ChenJY (2000) A protein kinase activity associated with Epstein-Barr virus BGLF4 phosphorylates the viral early antigen EA-D in vitro. J Virol 74: 3093–3104.

17. GershburgE, PaganoJS (2008) Conserved herpesvirus protein kinases. Biochim Biophys Acta 1784: 203–212.

18. RomakerD, SchregelV, MaurerK, AuerochsS, MarziA, et al. (2006) Analysis of the structure-activity relationship of four herpesviral UL97 subfamily protein kinases reveals partial but not full functional conservation. J Med Chem 49: 7044–7053.

19. KunyCV, ChinchillaK, CulbertsonMR, KalejtaRF (2010) Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases. PLoS pathogens 6: e1001092.

20. KawaguchiY, KatoK, TanakaM, KanamoriM, NishiyamaY, et al. (2003) Conserved protein kinases encoded by herpesviruses and cellular protein kinase cdc2 target the same phosphorylation site in eukaryotic elongation factor 1delta. J Virol 77: 2359–2368.

21. LeeCP, ChenJY, WangJT, KimuraK, TakemotoA, et al. (2007) Epstein-Barr virus BGLF4 kinase induces premature chromosome condensation through activation of condensin and topoisomerase II. J Virol 81: 5166–5180.

22. ChenPW, LinSJ, TsaiSC, LinJH, ChenMR, et al. (2010) Regulation of microtubule dynamics through phosphorylation on stathmin by Epstein-Barr virus kinase BGLF4. J Biol Chem 285: 10053–10063.

23. ZhuJ, LiaoG, ShanL, ZhangJ, ChenMR, et al. (2009) Protein array identification of substrates of the Epstein-Barr virus protein kinase BGLF4. J Virol 83: 5219–5231.

24. IwahoriS, MurataT, KudohA, SatoY, NakayamaS, et al. (2009) Phosphorylation of p27Kip1 by Epstein-Barr virus protein kinase induces its degradation through SCFSkp2 ubiquitin ligase actions during viral lytic replication. J Biol Chem 284: 18923–18931.

25. KudohA, DaikokuT, IshimiY, KawaguchiY, ShirataN, et al. (2006) Phosphorylation of MCM4 at sites inactivating DNA helicase activity of the MCM4-MCM6-MCM7 complex during Epstein-Barr virus productive replication. Journal of virology 80: 10064–10072.

26. KatoK, KawaguchiY, TanakaM, IgarashiM, YokoyamaA, et al. (2001) Epstein-Barr virus-encoded protein kinase BGLF4 mediates hyperphosphorylation of cellular elongation factor 1delta (EF-1delta): EF-1delta is universally modified by conserved protein kinases of herpesviruses in mammalian cells. J Gen Virol 82: 1457–1463.

27. LeeCP, HuangYH, LinSF, ChangY, ChangYH, et al. (2008) Epstein-Barr virus BGLF4 kinase induces disassembly of the nuclear lamina to facilitate virion production. J Virol 82: 11913–11926.

28. MengQ, HagemeierSR, KunyCV, KalejtaRF, KenneySC (2010) Simian virus 40 T/t antigens and lamin A/C small interfering RNA rescue the phenotype of an Epstein-Barr virus protein kinase (BGLF4) mutant. J Virol 84: 4524–4533.

29. SunX, BristolJA, IwahoriS, HagemeierSR, MengQ, et al. (2013) Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells. Journal of virology 87: 10126–10138.

30. KugaT, NozakiN, MatsushitaK, NomuraF, TomonagaT (2010) Phosphorylation statuses at different residues of lamin B2, B1, and A/C dynamically and independently change throughout the cell cycle. Experimental cell research 316: 2301–2312.

31. GershburgE, RaffaS, TorrisiMR, PaganoJS (2007) Epstein-Barr virus-encoded protein kinase (BGLF4) is involved in production of infectious virus. J Virol 81: 5407–5412.

32. MurataT, IsomuraH, YamashitaY, ToyamaS, SatoY, et al. (2009) Efficient production of infectious viruses requires enzymatic activity of Epstein-Barr virus protein kinase. Virology 389: 75–81.

33. WangJT, ChuangYC, ChenKL, LuCC, DoongSL, et al. (2010) Characterization of Epstein-Barr virus BGLF4 kinase expression control at the transcriptional and translational levels. J Gen Virol 91: 2186–2196.

34. WangJT, YangPW, LeeCP, HanCH, TsaiCH, et al. (2005) Detection of Epstein-Barr virus BGLF4 protein kinase in virus replication compartments and virus particles. J Gen Virol 86: 3215–3225.

35. SugimotoA, SatoY, KandaT, MurataT, NaritaY, et al. (2013) Different distributions of Epstein-Barr virus early and late gene transcripts within viral replication compartments. Journal of virology 87: 6693–6699.

36. YangPW, ChangSS, TsaiCH, ChaoYH, ChenMR (2008) Effect of phosphorylation on the transactivation activity of Epstein-Barr virus BMRF1, a major target of the viral BGLF4 kinase. J Gen Virol 89: 884–895.

37. AsaiR, KatoA, KawaguchiY (2009) Epstein-Barr virus protein kinase BGLF4 interacts with viral transactivator BZLF1 and regulates its transactivation activity. J Gen Virol 90: 1575–1581.

38. YueW, GershburgE, PaganoJS (2005) Hyperphosphorylation of EBNA2 by Epstein-Barr virus protein kinase suppresses transactivation of the LMP1 promoter. J Virol 79: 5880–5885.

39. KatoK, YokoyamaA, TohyaY, AkashiH, NishiyamaY, et al. (2003) Identification of protein kinases responsible for phosphorylation of Epstein-Barr virus nuclear antigen leader protein at serine-35, which regulates its coactivator function. J Gen Virol 84: 3381–3392.

40. WangJT, DoongSL, TengSC, LeeCP, TsaiCH, et al. (2009) Epstein-Barr virus BGLF4 kinase suppresses the interferon regulatory factor 3 signaling pathway. J Virol 83: 1856–1869.

41. WangJT, ChangLS, ChenCJ, DoongSL, ChangCW, et al. (2013) Glycogen synthase kinase 3 negatively regulates IFN regulatory factor 3 transactivation through phosphorylation at its linker region. Innate immunity 20 (1) 78–87.

42. ChangLS, WangJT, DoongSL, LeeCP, ChangCW, et al. (2012) Epstein-Barr Virus BGLF4 Kinase Down-regulates NF-kappaB Transactivation through Phosphorylation of Coactivator UXT. Journal of virology 86: 12176–12186.

43. MounceBC, MbokoWP, BigleyTM, TerhuneSS, TarakanovaVL (2013) A conserved gammaherpesvirus protein kinase targets histone deacetylases 1 and 2 to facilitate viral replication in primary macrophages. Journal of virology 87: 7314–7325.

44. LiR, ZhuJ, XieZ, LiaoG, LiuJ, et al. (2011) Conserved Herpesvirus Kinases Target the DNA Damage Response Pathway and TIP60 Histone Acetyltransferase to Promote Virus Replication. Cell host & microbe 10: 390–400.

45. LiR, WangL, LiaoG, GuzzoCM, MatunisMJ, et al. (2012) SUMO binding by the Epstein-Barr virus protein kinase BGLF4 is crucial for BGLF4 function. Journal of virology 86: 5412–5421.

46. HagemeierSR, BarlowEA, MengQ, KenneySC (2012) The cellular ataxia telangiectasia-mutated kinase promotes epstein-barr virus lytic reactivation in response to multiple different types of lytic reactivation-inducing stimuli. Journal of virology 86: 13360–13370.

47. FeederleR, Mehl-LautschamAM, BannertH, DelecluseHJ (2009) The Epstein-Barr virus protein kinase BGLF4 and the exonuclease BGLF5 have opposite effects on the regulation of viral protein production. J Virol 83: 10877–10891.

48. LeeCP, ChenMR (2010) Escape of herpesviruses from the nucleus. Reviews in medical virology 20: 214–230.

49. RoweM, GlaunsingerB, van LeeuwenD, ZuoJ, SweetmanD, et al. (2007) Host shutoff during productive Epstein-Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc Natl Acad Sci U S A 104: 3366–3371.

50. CountrymanJ, GradovilleL, Bhaduri-McIntoshS, YeJ, HestonL, et al. (2009) Stimulus duration and response time independently influence the kinetics of lytic cycle reactivation of Epstein-Barr virus. Journal of virology 83: 10694–10709.

51. YeJ, GradovilleL, DaigleD, MillerG (2007) De novo protein synthesis is required for lytic cycle reactivation of Epstein-Barr virus, but not Kaposi's sarcoma-associated herpesvirus, in response to histone deacetylase inhibitors and protein kinase C agonists. Journal of virology 81: 9279–9291.

52. GershburgE, PaganoJS (2002) Phosphorylation of the Epstein-Barr virus (EBV) DNA polymerase processivity factor EA-D by the EBV-encoded protein kinase and effects of the L-riboside benzimidazole 1263W94. J Virol 76: 998–1003.

53. CarreraAC, AlexandrovK, RobertsTM (1993) The conserved lysine of the catalytic domain of protein kinases is actively involved in the phosphotransfer reaction and not required for anchoring ATP. Proc Natl Acad Sci U S A 90: 442–446.

54. El-GuindyA, Ghiassi-NejadM, GoldenS, DelecluseHJ, MillerG (2013) Essential role of rta in lytic DNA replication of epstein-barr virus. J Virol 87: 208–223.

55. NeuhierlB, DelecluseHJ (2006) The Epstein-Barr virus BMRF1 gene is essential for lytic virus replication. Journal of virology 80: 5078–5081.

56. LengN, DawsonJA, ThomsonJA, RuottiV, RissmanAI, et al. (2013) EBSeq: an empirical Bayes hierarchical model for inference in RNA-seq experiments. Bioinformatics 29: 1035–1043.

57. LiB, DeweyCN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC bioinformatics 12: 323.

58. YuanJ, Cahir-McFarlandE, ZhaoB, KieffE (2006) Virus and cell RNAs expressed during Epstein-Barr virus replication. Journal of virology 80: 2548–2565.

59. LoesingJB, Di FioreS, RitterK, FischerR, KleinesM (2009) Epstein-Barr virus BDLF2-BMRF2 complex affects cellular morphology. The Journal of general virology 90: 1440–1449.

60. JohannsenE, LuftigM, ChaseMR, WeickselS, Cahir-McFarlandE, et al. (2004) Proteins of purified Epstein-Barr virus. Proc Natl Acad Sci U S A 101: 16286–16291.

61. BeisserPS, VerzijlD, GruijthuijsenYK, BeukenE, SmitMJ, et al. (2005) The Epstein-Barr virus BILF1 gene encodes a G protein-coupled receptor that inhibits phosphorylation of RNA-dependent protein kinase. Journal of virology 79: 441–449.

62. O'GradyT, CaoS, StrongMJ, ConchaM, WangX, et al. (2014) Global Bidirectional Transcription of the Epstein-Barr Virus Genome during Reactivation. Journal of virology 88: 1604–1616.

63. ChenMR, HsuTY, ChenJY, YangCS (1990) Molecular characterization of a cDNA clone encoding the Epstein-Barr virus (EBV) DNase. J Virol Methods 29: 127–141.

64. HaqueM, WangV, DavisDA, ZhengZM, YarchoanR (2006) Genetic organization and hypoxic activation of the Kaposi's sarcoma-associated herpesvirus ORF34-37 gene cluster. J Virol 80: 7037–7051.

65. HaqueM, KousoulasKG (2013) The Kaposi's sarcoma-associated herpesvirus ORF34 protein binds to HIF-1alpha and causes its degradation via the proteasome pathway. Journal of virology 87: 2164–2173.

66. FrancisAL, GradovilleL, MillerG (1997) Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. J Virol 71: 3054–3061.

67. FeederleR, KostM, BaumannM, JanzA, DrouetE, et al. (2000) The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. Embo J 19: 3080–3089.

68. DelecluseHJ, HilsendegenT, PichD, ZeidlerR, HammerschmidtW (1998) Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A 95: 8245–8250.

69. PearsonGR, VromanB, ChaseB, SculleyT, HummelM, et al. (1983) Identification of polypeptide components of the Epstein-Barr virus early antigen complex with monoclonal antibodies. J Virol 47: 193–201.

70. SongY, NagyM, NiW, TyagiNK, FentonWA, et al. (2013) Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proceedings of the National Academy of Sciences of the United States of America 110: 5428–5433.

71. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25: 1105–1111.

72. LangmeadB, SalzbergSL (2012) Fast gapped-read alignment with Bowtie 2. Nature methods 9: 357–359.

73. BaerR, BankierAT, BigginMD, DeiningerPL, FarrellPJ, et al. (1984) DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310: 207–211.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2014 Číslo 8
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#