Progressive Accumulation of Activated ERK2 within Highly Stable ORF45-Containing Nuclear Complexes Promotes Lytic Gammaherpesvirus Infection

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In this study, we find that lytic RRV infection leads to selective and progressive accumulation of pERK2 within RRV ORF45 (R45)-containing nuclear complexes in infected cells. In these complexes, pERK2 decays with first order kinetics and a half-life of nearly 3 hours, suggesting a highly stable complex with a slow R45 off-rate, while pERK1 decays with a half-life of less than 30 minutes, consistent with its accessibility to cellular phosphatases. We further describe that despite the apparent sequestration of pERK2 within the R45 complexes, downstream activation of pERK nuclear substrates remains robust, promoting virion production. Using confocal microscopy and FRET analyses, we show that R45 closely interacts with both pERK2 and pRSK2 in the nucleus in heterodimeric or heterotrimeric complexes. Lastly, although we demonstrate that RSK ectopic overexpression augments the levels of pERK2 in 293 cells co-transfected with R45, its role in ERK2 activation and virion production during RRV infection is not essential, in apparent contrast to its requirement during KSHV infection.

Vyšlo v časopise: Progressive Accumulation of Activated ERK2 within Highly Stable ORF45-Containing Nuclear Complexes Promotes Lytic Gammaherpesvirus Infection. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004066
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004066

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1. WoodsonEN, KedesDH (2012) Distinct roles for extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the structure and production of a primate gammaherpesvirus. J Virol 86 : 9721–9736.

2. CullenBR (2011) Herpesvirus microRNAs: phenotypes and functions. Curr Opin Virol 1 : 211–215.

3. OhsakiE, UedaK (2012) Kaposi's Sarcoma-Associated Herpesvirus Genome Replication, Partitioning, and Maintenance in Latency. Front Microbiol 3 : 7.

4. RamalingamD, Kieffer-KwonP, ZiegelbauerJM (2012) Emerging themes from EBV and KSHV microRNA targets. Viruses 4 : 1687–1710.

5. DiMaioTA, GutierrezKD, LagunoffM (2011) Latent KSHV infection of endothelial cells induces integrin beta3 to activate angiogenic phenotypes. PLoS Pathog 7: e1002424.

6. DupinN, DissTL, KellamP, TulliezM, DuMQ, et al. (2000) HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood 95 : 1406–1412.

7. MillerG, El-GuindyA, CountrymanJ, YeJ, GradovilleL (2007) Lytic cycle switches of oncogenic human gammaherpesviruses. Adv Cancer Res 97 : 81–109.

8. OlsenSJ, SaridR, ChangY, MoorePS (2000) Evaluation of the latency-associated nuclear antigen (ORF73) of Kaposi's sarcoma-associated herpesvirus by peptide mapping and bacterially expressed recombinant western blot assay. J Infect Dis 182 : 306–310.

9. WenKW, DamaniaB (2010) Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett 289 : 140–150.

10. DesrosiersRC, SassevilleVG, CzajakSC, ZhangX, MansfieldKG, et al. (1997) A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma-associated herpesvirus. J Virol 71 : 9764–9769.

11. YuF, HaradaJN, BrownHJ, DengH, SongMJ, et al. (2007) Systematic identification of cellular signals reactivating Kaposi sarcoma-associated herpesvirus. PLoS Pathog 3: e44.

12. PanH, XieJ, YeF, GaoSJ (2006) Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J Virol 80 : 5371–5382.

13. SadagopanS, Sharma-WaliaN, VeettilMV, RaghuH, SivakumarR, et al. (2007) Kaposi's sarcoma-associated herpesvirus induces sustained NF-kappaB activation during de novo infection of primary human dermal microvascular endothelial cells that is essential for viral gene expression. J Virol 81 : 3949–3968.

14. Sharma-WaliaN, KrishnanHH, NaranattPP, ZengL, SmithMS, et al. (2005) ERK1/2 and MEK1/2 induced by Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) early during infection of target cells are essential for expression of viral genes and for establishment of infection. J Virol 79 : 10308–10329.

15. AplinAE, StewartSA, AssoianRK, JulianoRL (2001) Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol 153 : 273–282.

16. SegerR, KrebsEG (1995) The MAPK signaling cascade. FASEB J 9 : 726–735.

17. YoonS, SegerR (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24 : 21–44.

18. BoutrosT, ChevetE, MetrakosP (2008) Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev 60 : 261–310.

19. CargnelloM, RouxPP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75 : 50–83.

20. CohenA, BrodieC, SaridR (2006) An essential role of ERK signalling in TPA-induced reactivation of Kaposi's sarcoma-associated herpesvirus. J Gen Virol 87 : 795–802.

21. KarinM, LiuZ, ZandiE (1997) AP-1 function and regulation. Curr Opin Cell Biol 9 : 240–246.

22. WangSE, WuFY, ChenH, ShamayM, ZhengQ, et al. (2004) Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway. J Virol 78 : 4248–4267.

23. XieJ, PanH, YooS, GaoSJ (2005) Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol 79 : 15027–15037.

24. KuangE, WuF, ZhuF (2009) Mechanism of sustained activation of ribosomal S6 kinase (RSK) and ERK by kaposi sarcoma-associated herpesvirus ORF45: multiprotein complexes retain active phosphorylated ERK AND RSK and protect them from dephosphorylation. J Biol Chem 284 : 13958–13968.

25. LuoH, YanagawaB, ZhangJ, LuoZ, ZhangM, et al. (2002) Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. J Virol 76 : 3365–3373.

26. PleschkaS, WolffT, EhrhardtC, HobomG, PlanzO, et al. (2001) Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 3 : 301–305.

27. RadyPL, YenA, MartinRW3rd, NedelcuI, HughesTK, et al. (1995) Herpesvirus-like DNA sequences in classic Kaposi's sarcomas. J Med Virol 47 : 179–183.

28. FordPW, BryanBA, DysonOF, WeidnerDA, ChintalgattuV, et al. (2006) Raf/MEK/ERK signalling triggers reactivation of Kaposi's sarcoma-associated herpesvirus latency. J Gen Virol 87 : 1139–1144.

29. KrishnanHH, NaranattPP, SmithMS, ZengL, BloomerC, et al. (2004) Concurrent expression of latent and a limited number of lytic genes with immune modulation and antiapoptotic function by Kaposi's sarcoma-associated herpesvirus early during infection of primary endothelial and fibroblast cells and subsequent decline of lytic gene expression. J Virol 78 : 3601–3620.

30. CannonM, PhilpottNJ, CesarmanE (2003) The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol 77 : 57–67.

31. CannonML, CesarmanE (2004) The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene 23 : 514–523.

32. KuangE, TangQ, MaulGG, ZhuF (2008) Activation of p90 ribosomal S6 kinase by ORF45 of Kaposi's sarcoma-associated herpesvirus and its role in viral lytic replication. J Virol 82 : 1838–1850.

33. ZhuFX, SathishN, YuanY (2010) Antagonism of host antiviral responses by Kaposi's sarcoma-associated herpesvirus tegument protein ORF45. PLoS One 5: e10573.

34. ZhuFX, YuanY (2003) The ORF45 protein of Kaposi's sarcoma-associated herpesvirus is associated with purified virions. J Virol 77 : 4221–4230.

35. O'ConnorCM, KedesDH (2006) Mass spectrometric analyses of purified rhesus monkey rhadinovirus reveal 33 virion-associated proteins. J Virol 80 : 1574–1583.

36. SathishN, WangX, YuanY (2012) Tegument Proteins of Kaposi's Sarcoma-Associated Herpesvirus and Related Gamma-Herpesviruses. Front Microbiol 3 : 98.

37. ZhuFX, ChongJM, WuL, YuanY (2005) Virion proteins of Kaposi's sarcoma-associated herpesvirus. J Virol 79 : 800–811.

38. ParsonsCH, AdangLA, OverdevestJ, O'ConnorCM, TaylorJRJr, et al. (2006) KSHV targets multiple leukocyte lineages during long-term productive infection in NOD/SCID mice. J Clin Invest 116 : 1963–1973.

39. TomescuC, LawWK, KedesDH (2003) Surface downregulation of major histocompatibility complex class I, PE-CAM, and ICAM-1 following de novo infection of endothelial cells with Kaposi's sarcoma-associated herpesvirus. J Virol 77 : 9669–9684.

40. DeWireSM, MoneyES, KrallSP, DamaniaB (2003) Rhesus monkey rhadinovirus (RRV): construction of a RRV-GFP recombinant virus and development of assays to assess viral replication. Virology 312 : 122–134.

41. SunY, BookerCF, KumariS, DayRN, DavidsonM, et al. (2009) Characterization of an orange acceptor fluorescent protein for sensitized spectral fluorescence resonance energy transfer microscopy using a white-light laser. J Biomed Opt 14 : 054009.

42. ChenY, PeriasamyA (2006) Intensity range based quantitative FRET data analysis to localize protein molecules in live cell nuclei. J Fluoresc 16 : 95–104.

43. PeriasamyA, WallrabeH, ChenY, BarrosoM (2008) Chapter 22: Quantitation of protein-protein interactions: confocal FRET microscopy. Methods Cell Biol 89 : 569–598.

44. SunY, WallrabeH, BookerCF, DayRN, PeriasamyA (2010) Three-color spectral FRET microscopy localizes three interacting proteins in living cells. Biophys J 99 : 1274–1283.

45. AlexanderL, DenekampL, KnappA, AuerbachMR, DamaniaB, et al. (2000) The primary sequence of rhesus monkey rhadinovirus isolate 26–95: sequence similarities to Kaposi's sarcoma-associated herpesvirus and rhesus monkey rhadinovirus isolate 17577. J Virol 74 : 3388–3398.

46. BilelloJP, LangSM, WangF, AsterJC, DesrosiersRC (2006) Infection and persistence of rhesus monkey rhadinovirus in immortalized B-cell lines. J Virol 80 : 3644–3649.

47. EbisuyaM, KondohK, NishidaE (2005) The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J Cell Sci 118 : 2997–3002.

48. RouxPP, BlenisJ (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68 : 320–344.

49. RubinfeldH, SegerR (2005) The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol 31 : 151–174.

50. TheodosiouA, AshworthA (2002) MAP kinase phosphatases. Genome Biol 3: REVIEWS3009.

51. LymanMG, RandallJA, CaltonCM, BanfieldBW (2006) Localization of ERK/MAP kinase is regulated by the alphaherpesvirus tegument protein Us2. J Virol 80 : 7159–7168.

52. ChenRH, SarneckiC, BlenisJ (1992) Nuclear localization and regulation of erk -⁠ and rsk-encoded protein kinases. Mol Cell Biol 12 : 915–927.

53. RomeoY, MoreauJ, ZindyPJ, Saba-El-LeilM, LavoieG, et al. (2013) RSK regulates activated BRAF signalling to mTORC1 and promotes melanoma growth. Oncogene 32 : 2917–2926.

54. RomeoY, ZhangX, RouxPP (2012) Regulation and function of the RSK family of protein kinases. Biochem J 441 : 553–569.

55. ChrestensenCA, EschenroederA, RossWG, UedaT, Watanabe-FukunagaR, et al. (2007) Loss of MNK function sensitizes fibroblasts to serum-withdrawal induced apoptosis. Genes Cells 12 : 1133–1140.

56. WaskiewiczAJ, JohnsonJC, PennB, MahalingamM, KimballSR, et al. (1999) Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol Cell Biol 19 : 1871–1880.

57. WalshD, MohrI (2004) Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells. Genes Dev 18 : 660–672.

58. SalinasS, Briancon-MarjolletA, BossisG, LopezMA, PiechaczykM, et al. (2004) SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1. J Cell Biol 165 : 767–773.

59. ChandrianiS, GanemD (2007) Host transcript accumulation during lytic KSHV infection reveals several classes of host responses. PLoS One 2: e811.

60. GlaunsingerB, ChavezL, GanemD (2005) The exonuclease and host shutoff functions of the SOX protein of Kaposi's sarcoma-associated herpesvirus are genetically separable. J Virol 79 : 7396–7401.

61. BoutrosT, NantelA, EmadaliA, TzimasG, ConzenS, et al. (2008) The MAP kinase phosphatase-1 MKP-1/DUSP1 is a regulator of human liver response to transplantation. Am J Transplant 8 : 2558–2568.

62. CauntCJ, KeyseSM (2013) Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J 280 : 489–504.

63. ChenH, PuhlHL3rd, KoushikSV, VogelSS, IkedaSR (2006) Measurement of FRET efficiency and ratio of donor to acceptor concentration in living cells. Biophys J 91: L39–41.

64. ChenY, MauldinJP, DayRN, PeriasamyA (2007) Characterization of spectral FRET imaging microscopy for monitoring nuclear protein interactions. J Microsc 228 : 139–152.

65. SunY, PeriasamyA (2010) Additional correction for energy transfer efficiency calculation in filter-based Forster resonance energy transfer microscopy for more accurate results. J Biomed Opt 15 : 020513.

66. SunY, WallrabeH, SeoSA, PeriasamyA (2011) FRET microscopy in 2010: the legacy of Theodor Forster on the 100th anniversary of his birth. Chemphyschem 12 : 462–474.

67. LiangQ, FuB, WuF, LiX, YuanY, et al. (2012) ORF45 of Kaposi's Sarcoma–Associated Herpesvirus Inhibits Phosphorylation of IRF7 by IKK{varepsilon} and TBK1 as an Alternative Substrate. J Virol 77 : 4221–4230.

68. BarberSA, BruettL, DouglassBR, HerbstDS, ZinkMC, et al. (2002) Visna virus-induced activation of MAPK is required for virus replication and correlates with virus-induced neuropathology. J Virol 76 : 817–828.

69. AbkhezrM, KeramatiAR, OstadSN, DavoodiJ, GhahremaniMH (2010) The time course of Akt and ERK activation on XIAP expression in HEK 293 cell line. Mol Biol Rep 37 : 2037–2042.

70. SchumannM, DobbelsteinM (2006) Adenovirus-induced extracellular signal-regulated kinase phosphorylation during the late phase of infection enhances viral protein levels and virus progeny. Cancer Res 66 : 1282–1288.

71. MarshallCJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80 : 179–185.

72. BossV, RobackJD, YoungAN, RobackLJ, WeisenhornDM, et al. (2001) Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to AP-1 and CREB binding elements in pheochromocytoma (PC12) cells. J Neurosci 21 : 18–26.

73. TraverseS, SeedorfK, PatersonH, MarshallCJ, CohenP, et al. (1994) EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol 4 : 694–701.

74. MurphyLO, SmithS, ChenRH, FingarDC, BlenisJ (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol 4 : 556–564.

75. YasuiH, KatohH, YamaguchiY, AokiJ, FujitaH, et al. (2001) Differential responses to nerve growth factor and epidermal growth factor in neurite outgrowth of PC12 cells are determined by Rac1 activation systems. J Biol Chem 276 : 15298–15305.

76. MarkMD, LiuY, WongST, HindsTR, StormDR (1995) Stimulation of neurite outgrowth in PC12 cells by EGF and KCl depolarization: a Ca(2+)-independent phenomenon. J Cell Biol 130 : 701–710.

77. SharrocksAD (2006) Cell cycle: sustained ERK signalling represses the inhibitors. Curr Biol 16: R540–542.

78. CayrolC, FlemingtonEK (1996) The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors. Embo J 15 : 2748–2759.

79. FlemingtonEK (2001) Herpesvirus lytic replication and the cell cycle: arresting new developments. J Virol 75 : 4475–4481.

80. IzumiyaY, LinSF, EllisonTJ, LevyAM, MayeurGL, et al. (2003) Cell cycle regulation by Kaposi's sarcoma-associated herpesvirus K-bZIP: direct interaction with cyclin-CDK2 and induction of G1 growth arrest. J Virol 77 : 9652–9661.

81. LuM, ShenkT (1999) Human cytomegalovirus UL69 protein induces cells to accumulate in G1 phase of the cell cycle. J Virol 73 : 676–683.

82. ZehoraiE, YaoZ, PlotnikovA, SegerR (2010) The subcellular localization of MEK and ERK–a novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol Cell Endocrinol 314 : 213–220.

83. BaisC, SantomassoB, CosoO, ArvanitakisL, RaakaEG, et al. (1998) G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391 : 86–89.

84. JhamBC, MaT, HuJ, ChaisuparatR, FriedmanER, et al. (2011) Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma. PLoS One 6: e19103.

85. LiX, ZhuF (2009) Identification of the nuclear export and adjacent nuclear localization signals for ORF45 of Kaposi's sarcoma-associated herpesvirus. J Virol 83 : 2531–2539.

86. LaurentAM, MadjarJJ, GrecoA (1998) Translational control of viral and host protein synthesis during the course of herpes simplex virus type 1 infection: evidence that initiation of translation is the limiting step. J Gen Virol 79(Pt 11): 2765–2775.