Nucleophosmin Phosphorylation by v-Cyclin-CDK6 Controls KSHV Latency

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Nucleophosmin (NPM) is a multifunctional nuclear phosphoprotein and a histone chaperone implicated in chromatin organization and transcription control. Oncogenic Kaposi's sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). In the infected host cell KSHV displays two modes of infection, the latency and productive viral replication phases, involving extensive viral DNA replication and gene expression. A sustained balance between latency and reactivation to the productive infection state is essential for viral persistence and KSHV pathogenesis. Our study demonstrates that the KSHV v-cyclin and cellular CDK6 kinase phosphorylate NPM on threonine 199 (Thr199) in de novo and naturally KSHV-infected cells and that NPM is phosphorylated to the same site in primary KS tumors. Furthermore, v-cyclin-mediated phosphorylation of NPM engages the interaction between NPM and the latency-associated nuclear antigen LANA, a KSHV-encoded repressor of viral lytic replication. Strikingly, depletion of NPM in PEL cells leads to viral reactivation, and production of new infectious virus particles. Moreover, the phosphorylation of NPM negatively correlates with the level of spontaneous viral reactivation in PEL cells. This work demonstrates that NPM is a critical regulator of KSHV latency via functional interactions with v-cyclin and LANA.

Vyšlo v časopise: Nucleophosmin Phosphorylation by v-Cyclin-CDK6 Controls KSHV Latency. PLoS Pathog 6(3): e32767. doi:10.1371/journal.ppat.1000818
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000818

Souhrn

Zdroje

1. BorerRA

LehnerCF

EppenbergerHM

NiggEA

1989 Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 56 379 390

2. GrisendiS

MecucciC

FaliniB

PandolfiPP

2006 Nucleophosmin and cancer. Nat Rev Cancer 6 493 505

3. OkudaM

HornHF

TaraporeP

TokuyamaY

SmulianAG

2000 Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 103 127 140

4. TokuyamaY

HornHF

KawamuraK

TaraporeP

FukasawaK

2001 Specific phosphorylation of nucleophosmin on Thr(199) by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication. J Biol Chem 276 21529 21537

5. AblashiDV

ChatlynneLG

WhitmanJEJr

CesarmanE

2002 Spectrum of Kaposi's sarcoma-associated herpesvirus, or human herpesvirus 8, diseases. Clin Microbiol Rev 15 439 464

6. ZhongW

WangH

HerndierB

GanemD

1996 Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in Kaposi sarcoma. Proc Natl Acad Sci U S A 93 6641 6646

7. DittmerDP

2003 Transcription profile of Kaposi's sarcoma-associated herpesvirus in primary Kaposi's sarcoma lesions as determined by real-time PCR arrays. Cancer Res 63 2010 2015

8. RenneR

ZhongW

HerndierB

McGrathM

AbbeyN

1996 Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 2 342 346

9. MillerG

El-GuindyA

CountrymanJ

YeJ

GradovilleL

2007 Lytic cycle switches of oncogenic human gammaherpesviruses(1). Adv Cancer Res 97 81 109

10. BallestasME

KayeKM

2001 Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol 75 3250 3258

11. BarberaAJ

ChodaparambilJV

Kelley-ClarkeB

JoukovV

WalterJC

2006 The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 311 856 861

12. BallestasME

ChatisPA

KayeKM

1999 Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284 641 644

13. YeFC

ZhouFC

YooSM

XieJP

BrowningPJ

2004 Disruption of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen leads to abortive episome persistence. J Virol 78 11121 11129

14. LanK

KuppersDA

VermaSC

RobertsonES

2004 Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen inhibits lytic replication by targeting Rta: a potential mechanism for virus-mediated control of latency. J Virol 78 6585 6594

15. LanK

KuppersDA

RobertsonES

2005 Kaposi's sarcoma-associated herpesvirus reactivation is regulated by interaction of latency-associated nuclear antigen with recombination signal sequence-binding protein Jkappa, the major downstream effector of the Notch signaling pathway. J Virol 79 3468 3478

16. GarberAC

ShuMA

HuJ

RenneR

2001 DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75 7882 7892

17. VermaSC

LanK

ChoudhuriT

RobertsonES

2006 Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats. J Virol 80 3445 3458

18. AnFQ

CompitelloN

HorwitzE

SramkoskiM

KnudsenES

2005 The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest. J Biol Chem 280 3862 3874

19. DittmerD

LagunoffM

RenneR

StaskusK

HaaseA

1998 A cluster of latently expressed genes in Kaposi's sarcoma-associated herpesvirus. J Virol 72 8309 8315

20. GrundhoffA

GanemD

2001 Mechanisms governing expression of the v-FLIP gene of Kaposi's sarcoma-associated herpesvirus. J Virol 75 1857 1863

21. PearceM

MatsumuraS

WilsonAC

2005 Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi's sarcoma-associated herpesvirus originate from a common promoter. J Virol 79 14457 14464

22. MittnachtS

BoshoffC

2000 Viral cyclins. Rev Med Virol 10 175 184

23. VerschurenEW

JonesN

EvanGI

2004 The cell cycle and how it is steered by Kaposi's sarcoma-associated herpesvirus cyclin. J Gen Virol 85 1347 1361

24. JarviluomaA

OjalaPM

2006 Cell signaling pathways engaged by KSHV. Biochim Biophys Acta 1766 140 158

25. KurkiS

PeltonenK

LatonenL

KiviharjuTM

OjalaPM

2004 Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5 465 475

26. SarekG

JarviluomaA

OjalaPM

2006 KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 107 725 732

27. CuomoME

KnebelA

MorriceN

PatersonH

CohenP

2008 p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. Nat Cell Biol 10 723 730

28. OkuwakiM

TsujimotoM

NagataK

2002 The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Mol Biol Cell 13 2016 2030

29. TaraporeP

ShinmuraK

SuzukiH

TokuyamaY

KimSH

2006 Thr199 phosphorylation targets nucleophosmin to nuclear speckles and represses pre-mRNA processing. FEBS Lett 580 399 409

30. VieiraJ

O'HearnPM

2004 Use of the red fluorescent protein as a marker of Kaposi's sarcoma-associated herpesvirus lytic gene expression. Virology 325 225 240

31. GodfreyA

AndersonJ

PapanastasiouA

TakeuchiY

BoshoffC

2005 Inhibiting primary effusion lymphoma by lentiviral vectors encoding short hairpin RNA. Blood 105 2510 2518

32. TalbotSJ

WeissRA

KellamP

BoshoffC

1999 Transcriptional analysis of human herpesvirus-8 open reading frames 71, 72, 73, K14, and 74 in a primary effusion lymphoma cell line. Virology 257 84 94

33. KellerSA

SchattnerEJ

CesarmanE

2000 Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96 2537 2542

34. GuasparriI

KellerSA

CesarmanE

2004 KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199 993 1003

35. PlattGM

CannellE

CuomoME

SinghS

MittnachtS

2000 Detection of the human herpesvirus 8-encoded cyclin protein in primary effusion lymphoma-derived cell lines. Virology 272 257 266

36. JarviluomaA

KoopalS

RasanenS

MakelaTP

OjalaPM

2004 KSHV viral cyclin binds to p27KIP1 in primary effusion lymphomas. Blood 104 3349 3354

37. RaneSG

DubusP

MettusRV

GalbreathEJ

BodenG

1999 Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22 44 52

38. TsutsuiT

HesabiB

MoonsDS

PandolfiPP

HanselKS

1999 Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 19 7011 7019

39. MalumbresM

SotilloR

SantamariaD

GalanJ

CerezoA

2004 Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118 493 504

40. SiH

VermaSC

RobertsonES

2006 Proteomic analysis of the Kaposi's sarcoma-associated herpesvirus terminal repeat element binding proteins. J Virol 80 9017 9030

41. LiuH

TanBC

TsengKH

ChuangCP

YehCW

2007 Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep 8 394 400

42. LuF

DayL

GaoSJ

LiebermanPM

2006 Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription. J Virol 80 5273 5282

43. SwaminathanV

KishoreAH

FebithaKK

KunduTK

2005 Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol 25 7534 7545

44. ChengF

Weidner-GlundeM

VarjosaloM

RainioEM

LehtonenA

2009 KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA. PLoS Pathog 5 e1000324 doi:10.1371/journal.ppat.1000324

45. GwackY

ByunH

HwangS

LimC

ChoeJ

2001 CREB-binding protein and histone deacetylase regulate the transcriptional activity of Kaposi's sarcoma-associated herpesvirus open reading frame 50. J Virol 75 1909 1917

46. WaltonTH

MoenPTJr

FoxE

BodnarJW

1989 Interactions of minute virus of mice and adenovirus with host nucleoli. J Virol 63 3651 3660

47. MatthewsDA

2001 Adenovirus protein V induces redistribution of nucleolin and B23 from nucleolus to cytoplasm. J Virol 75 1031 1038

48. BevingtonJM

NeedhamPG

VerrillKC

CollacoRF

BasrurV

2007 Adeno-associated virus interactions with B23/Nucleophosmin: identification of sub-nucleolar virion regions. Virology 357 102 113

49. QiW

ShakalyaK

StejskalA

GoldmanA

BeeckS

2008 NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells. Oncogene 27 4210 4220

50. JianY

GaoZ

SunJ

ShenQ

FengF

2009 RNA aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells. Oncogene 28 4201 4211

51. CesarmanE

MoorePS

RaoPH

InghiramiG

KnowlesDM

1995 In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 86 2708 2714

52. CannonJS

CiufoD

HawkinsAL

GriffinCA

BorowitzMJ

2000 A new primary effusion lymphoma-derived cell line yields a highly infectious Kaposi's sarcoma herpesvirus-containing supernatant. J Virol 74 10187 10193

53. ArvanitakisL

MesriEA

NadorRG

SaidJW

AschAS

1996 Establishment and characterization of a primary effusion (body cavity-based) lymphoma cell line (BC-3) harboring kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) in the absence of Epstein-Barr virus. Blood 88 2648 2654

54. SarekG

KurkiS

EnbackJ

IotzovaG

HaasJ

2007 Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. J Clin Invest 117 1019 1028

55. KoopalS

FuruhjelmJH

JarviluomaA

JaamaaS

PyakurelP

2007 Viral oncogene-induced DNA damage response is activated in Kaposi sarcoma tumorigenesis. PLoS Pathog 3 1348 1360