Cyclin-Dependent Kinase Activity Controls the Onset of the HCMV Lytic Cycle

English version České info

The onset of human cytomegalovirus (HCMV) lytic infection is strictly synchronized with the host cell cycle. Infected G0/G1 cells support viral immediate early (IE) gene expression and proceed to the G1/S boundary where they finally arrest. In contrast, S/G2 cells can be infected but effectively block IE gene expression and this inhibition is not relieved until host cells have divided and reentered G1. During latent infection IE gene expression is also inhibited, and for reactivation to occur this block to IE gene expression must be overcome. It is only poorly understood which viral and/or cellular activities maintain the block to cell cycle or latency-associated viral IE gene repression and whether the two mechanisms may be linked. Here, we show that the block to IE gene expression during S and G2 phase can be overcome by both genotoxic stress and chemical inhibitors of cellular DNA replication, pointing to the involvement of checkpoint-dependent signaling pathways in controlling IE gene repression. Checkpoint-dependent rescue of IE expression strictly requires p53 and in the absence of checkpoint activation is mimicked by proteasomal inhibition in a p53 dependent manner. Requirement for the cyclin dependent kinase (CDK) inhibitor p21 downstream of p53 suggests a pivotal role for CDKs in controlling IE gene repression in S/G2 and treatment of S/G2 cells with the CDK inhibitor roscovitine alleviates IE repression independently of p53. Importantly, CDK inhibiton also overcomes the block to IE expression during quiescent infection of NTera2 (NT2) cells. Thus, a timely block to CDK activity not only secures phase specificity of the cell cycle dependent HCMV IE gene expression program, but in addition plays a hitherto unrecognized role in preventing the establishment of a latent-like state.

Vyšlo v časopise: Cyclin-Dependent Kinase Activity Controls the Onset of the HCMV Lytic Cycle. PLoS Pathog 6(9): e32767. doi:10.1371/journal.ppat.1001096
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001096

Souhrn

Zdroje

1. MocarskiES

ShenkT

PassRF

2007 Cytomegaloviruses.

KnipeDM

HowleyPM

GriffinDE

LambRA

MartinMA

RoizmanB

StrausSE

Fields virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA 2701 2772

2. MeierJL

StinskiMF

2006 Major immediate-early enhancer and its gene products. In Cytomegaloviruses: Molecular Biology and Immunology ed.

ReddehaseM

Norfolk Caister Academic Press 151 166

3. BegoM

MaciejewskiJ

KhaiboullinaS

PariG

St JeorS

2005 Characterization of an antisense transcript spanning the UL81-82 locus of human cytomegalovirus. J Virol 79 11022 11034

4. KondoK

XuJ

MocarskiES

1996 Human cytomegalovirus latent gene expression in granulocyte-macrophage progenitors in culture and in seropositive individuals. Proc Natl Acad Sci U S A 93 11137 11142

5. PetrucelliA

RakM

GraingerL

GoodrumF

2009 Characterization of a novel Golgi apparatus-localized latency determinant encoded by human cytomegalovirus. J Virol 83 5615 5629

6. JenkinsC

AbendrothA

SlobedmanB

2004 A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection. J Virol 78 1440 1447

7. KellerMJ

WuAW

AndrewsJI

McGonagillPW

TibesarEE

2007 Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway. J Virol 81 6669 6681

8. YuanJ

LiuX

WuAW

McGonagillPW

KellerMJ

2009 Breaking human cytomegalovirus major immediate-early gene silence by vasoactive intestinal peptide stimulation of the protein kinase A-CREB-TORC2 signaling cascade in human pluripotent embryonal NTera2 cells. J Virol 83 6391 6403

9. 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

10. GrilloneLR

LanzR

2001 Fomivirsen. Drugs Today (Barc) 37 245 255

11. 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

12. 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

13. WiebuschL

NeuwirthA

GrabenhenrichL

VoigtS

HagemeierC

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

14. NayakBK

DasGM

2002 Stabilization of p53 and transactivation of its target genes in response to replication blockade. Oncogene 21 7226 7229

15. ByunTS

PacekM

YeeMC

WalterJC

CimprichKA

2005 Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19 1040 1052

16. LevineAJ

OrenM

2009 The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9 749 758

17. WiebuschL

HagemeierC

2010 P53 and p21 dependent premature APC/C-Cdh1 activation is part of the long term response to genotoxic stress. Oncogene 29 3477 3489

18. BrooksCL

GuW

2006 p53 ubiquitination: Mdm2 and beyond. Mol Cell 21 307 315

19. AbbasT

DuttaA

2009 p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9 400 414

20. BunzF

DutriauxA

LengauerC

WaldmanT

ZhouS

1998 Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282 1497 1501

21. RosenkeK

FortunatoEA

2004 Bromodeoxyuridine-labeled viral particles as a tool for visualization of the immediate-early events of human cytomegalovirus infection. J Virol 78 7818 7822

22. SanchezV

McElroyAK

YenJ

TamrakarS

ClarkCL

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

23. 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

24. KapasiAJ

SpectorDH

2008 Inhibition of the cyclin-dependent kinases at the beginning of human cytomegalovirus infection specifically alters the levels and localization of the RNA polymerase II carboxyl-terminal domain kinases cdk9 and cdk7 at the viral transcriptosome. J Virol 82 394 407

25. SavioM

CerriM

CazzaliniO

PeruccaP

StivalaLA

2006 Replication-dependent DNA damage response triggered by roscovitine induces an uncoupling of DNA replication proteins. Cell Cycle 5 2153 2159

26. Wesierska-GadekJ

SchmidG

2006 Dual action of the inhibitors of cyclin-dependent kinases: targeting of the cell-cycle progression and activation of wild-type p53 protein. Expert Opin Investig Drugs 15 23 38

27. DosaR

BurianK

GonczolE

2005 Human cytomegalovirus latency is associated with the state of differentiation of the host cells: an in vitro model in teratocarcinoma cells. Acta Microbiol Immunol Hung 52 397 406

28. GonczolE

AndrewsPW

PlotkinSA

1984 Cytomegalovirus replicates in differentiated but not in undifferentiated human embryonal carcinoma cells. Science 224 159 161

29. AndrewsPW

GonczolE

PlotkinSA

DignazioM

OosterhuisJW

1986 Differentiation of TERA-2 human embryonal carcinoma cells into neurons and HCMV permissive cells. Induction by agents other than retinoic acid. Differentiation 31 119 126

30. LaFeminaR

HaywardGS

1986 Constitutive and retinoic acid-inducible expression of cytomegalovirus immediate-early genes in human teratocarcinoma cells. J Virol 58 434 440

31. NelsonJA

GroudineM

1986 Transcriptional regulation of the human cytomegalovirus major immediate-early gene is associated with induction of DNase I-hypersensitive sites. Mol Cell Biol 6 452 461

32. SinclairJ

2008 Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol 41 180 185

33. MeierJL

2001 Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator. J Virol 75 1581 1593

34. MurphyJC

FischleW

VerdinE

SinclairJH

2002 Control of cytomegalovirus lytic gene expression by histone acetylation. Embo J 21 1112 1120

35. KalaszczynskaI

GengY

IinoT

MizunoS

ChoiY

2009 Cyclin A is redundant in fibroblasts but essential in hematopoietic and embryonic stem cells. Cell 138 352 365

36. WelmAL

TimchenkoNA

OnoY

SorimachiH

RadomskaHS

2002 C/EBPalpha is required for proteolytic cleavage of cyclin A by calpain 3 in myeloid precursor cells. J Biol Chem 277 33848 33856

37. BaldassarreG

BocciaA

BruniP

SandomenicoC

BaroneMV

2000 Retinoic acid induces neuronal differentiation of embryonal carcinoma cells by reducing proteasome-dependent proteolysis of the cyclin-dependent inhibitor p27. Cell Growth Differ 11 517 526

38. 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

39. 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

40. RechterS

ScottGM

EickhoffJ

ZielkeK

AuerochsS

2009 Cyclin-dependent Kinases Phosphorylate the Cytomegalovirus RNA Export Protein pUL69 and Modulate Its Nuclear Localization and Activity. J Biol Chem 284 8605 8613

41. SanchezV

SpectorDH

2006 Cyclin-dependent kinase activity is required for efficient expression and posttranslational modification of human cytomegalovirus proteins and for production of extracellular particles. J Virol 80 5886 5896

42. SanchezV

MahrJA

OrazioNI

SpectorDH

2007 Nuclear export of the human cytomegalovirus tegument protein pp65 requires cyclin-dependent kinase activity and the Crm1 exporter. J Virol 81 11730 11736

43. BresnahanWA

BoldoghI

ChiP

ThompsonEA

AlbrechtT

1997 Inhibition of cellular Cdk2 activity blocks human cytomegalovirus replication. Virology 231 239 247

44. HertelL

ChouS

MocarskiES

2007 Viral and cell cycle-regulated kinases in cytomegalovirus-induced pseudomitosis and replication. PLoS Pathog 3 e6

45. MarschallM

StammingerT

2009 Molecular targets for antiviral therapy of cytomegalovirus infections. Future Microbiol 4 731 742

46. SchangLM

St VincentMR

LacasseJJ

2006 Five years of progress on cyclin-dependent kinases and other cellular proteins as potential targets for antiviral drugs. Antivir Chem Chemother 17 293 320

47. HarperJW

ElledgeSJ

KeyomarsiK

DynlachtB

TsaiLH

1995 Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell 6 387 400

48. Wesierska-GadekJ

KrystofV

2009 Selective cyclin-dependent kinase inhibitors discriminating between cell cycle and transcriptional kinases: future reality or utopia? Ann N Y Acad Sci 1171 228 241

49. YamCH

FungTK

PoonRY

2002 Cyclin A in cell cycle control and cancer. Cell Mol Life Sci 59 1317 1326

50. JaultFM

JaultJM

RuchtiF

FortunatoEA

ClarkC

1995 Cytomegalovirus infection induces high levels of cyclins, phosphorylated Rb, and p53, leading to cell cycle arrest. J Virol 69 6697 6704

51. ShlapoberskyM

SandersR

ClarkC

SpectorDH

2006 Repression of HMGA2 gene expression by human cytomegalovirus involves the IE2 86-kilodalton protein and is necessary for efficient viral replication and inhibition of cyclin A transcription. J Virol 80 9951 9961

52. WiebuschL

HagemeierC

2001 The human cytomegalovirus immediate early 2 protein dissociates cellular DNA synthesis from cyclin-dependent kinase activation. Embo J 20 1086 1098

53. HsuCY

MechaliF

Bonne-AndreaC

2007 Nucleocytoplasmic shuttling of bovine papillomavirus E1 helicase downregulates viral DNA replication in S phase. J Virol 81 384 394

54. MaddikaS

PanigrahiS

WiechecE

WesselborgS

FischerU

2009 Unscheduled Akt-triggered activation of cyclin-dependent kinase 2 as a key effector mechanism of apoptin's anticancer toxicity. Mol Cell Biol 29 1235 1248

55. KalejtaRF

2008 Functions of human cytomegalovirus tegument proteins prior to immediate early gene expression. Curr Top Microbiol Immunol 325 101 115

56. FengX

SchroerJ

YuD

ShenkT

2006 Human cytomegalovirus pUS24 is a virion protein that functions very early in the replication cycle. J Virol 80 8371 8378

57. MungerJ

YuD

ShenkT

2006 UL26-deficient human cytomegalovirus produces virions with hypophosphorylated pp28 tegument protein that is unstable within newly infected cells. J Virol 80 3541 3548

58. StammingerT

GstaigerM

WeinzierlK

LorzK

WinklerM

2002 Open reading frame UL26 of human cytomegalovirus encodes a novel tegument protein that contains a strong transcriptional activation domain. J Virol 76 4836 4847

59. MitchellDP

SavarynJP

MoormanNJ

ShenkT

TerhuneSS

2009 Human cytomegalovirus UL28 and UL29 open reading frames encode a spliced mRNA and stimulate accumulation of immediate-early RNAs. J Virol 83 10187 10197

60. SchierlingK

StammingerT

MertensT

WinklerM

2004 Human cytomegalovirus tegument proteins ppUL82 (pp71) and ppUL35 interact and cooperatively activate the major immediate-early enhancer. J Virol 78 9512 9523

61. SchierlingK

BuserC

MertensT

WinklerM

2005 Human cytomegalovirus tegument protein ppUL35 is important for viral replication and particle formation. J Virol 79 3084 3096

62. BechtelJT

ShenkT

2002 Human cytomegalovirus UL47 tegument protein functions after entry and before immediate-early gene expression. J Virol 76 1043 1050

63. WangSK

DuhCY

WuCW

2004 Human cytomegalovirus UL76 encodes a novel virion-associated protein that is able to inhibit viral replication. J Virol 78 9750 9762

64. DaksisJI

PrestonCM

1992 Herpes simplex virus immediate early gene expression in the absence of transinduction by Vmw65 varies during the cell cycle. Virology 189 196 202

65. StaibF

RoblesAI

VarticovskiL

WangXW

ZeebergBR

2005 The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 65 10255 10264

66. MalletteFA

FerbeyreG

2007 The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle 6 1831 1836

67. Soderberg-NauclerC

2008 HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 41 218 223

68. 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