Viral Activation of MK2-hsp27-p115RhoGEF-RhoA Signaling Axis Causes Cytoskeletal Rearrangements, P-body Disruption and ARE-mRNA Stabilization

English version České info

We have only scratched the surface in understanding how viruses control host gene expression. Several viruses disrupt important sites of post-transcriptional control of gene expression known as processing bodies (PBs), but underlying regulatory mechanisms and biological relevance remain poorly understood in most cases. Our study shows that the Kaposin B (KapB) protein of Kaposi's sarcoma (KS)-associated herpesvirus, known to block the degradation of a class of labile host mRNAs, does so by constitutively activating a signaling axis involving MK2, hsp27, p115RhoGEF and RhoA, thereby dispersing PBs. Thus, PB disruption may support the secretion of host pro-inflammatory cytokines and angiogenic factors that underlies KS tumor formation. Furthermore, by activating RhoA, KapB also causes cytoskeletal rearrangements, accelerated cell migration and angiogenesis in an endothelial cell model. Our findings position KapB as a key contributor to viral reprogramming of endothelial cells.

Vyšlo v časopise: Viral Activation of MK2-hsp27-p115RhoGEF-RhoA Signaling Axis Causes Cytoskeletal Rearrangements, P-body Disruption and ARE-mRNA Stabilization. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004597
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004597

Souhrn

Zdroje

1. BoshoffC, SchulzTF, KennedyMM, GrahamAK, FisherC, et al. (1995) Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nat Med 1: 1274–1278.

2. CesarmanE, ChangY, MoorePS, SaidJW, KnowlesDM (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332: 1186–1191 doi:10.1056/NEJM199505043321802

3. SoulierJ, GrolletL, OksenhendlerE, CacoubP, Cazals-HatemD, et al. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86: 1276–1280.

4. SpeckSH, GanemD (2010) Viral Latency and Its Regulation: Lessons from the Gamma-Herpesviruses. Cell Host and Microbe 8: 100–115 doi:10.1016/j.chom.2010.06.014

5. AriasC, WeisburdB, Stern-GinossarN, MercierA, BellareP, et al. (2014) KSHV 2.0: A Comprehensive Annotation of the Kaposi's Sarcoma-Associated Herpesvirus Genome Using Next- Generation Sequencing Reveals Novel Genomic and Functional Features. PLoS Pathog 10: 1–23.

6. UmbachJL, CullenBR (2010) In-depth analysis of Kaposi's sarcoma-associated herpesvirus microRNA expression provides insights into the mammalian microRNA-processing machinery. Journal of Virology 84: 695–703 doi:10.1128/JVI.02013-09

7. GanemD (2010) KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest 120: 939–949 doi:10.1172/JCI40567

8. OjalaPM, SchulzTF (2014) Manipulation of endothelial cells by KSHV: Implications for angiogenesis and aberrant vascular differentiation. Seminars in Cancer Biology 26C: 69–77 doi:10.1016/j.semcancer.2014.01.008

9. GrossmannC, PodgrabinskaS, SkobeM, GanemD (2006) Activation of NF- κB by the Latent vFLIP Gene of Kaposi's Sarcoma-Associated Herpesvirus Is Required for the Spindle Shape of Virus-Infected Endothelial Cells and Contributes to Their Proinflammatory Phenotype. Journal of Virology 80: 7179–7185 doi:10.1128/JVI.01603-05

10. NaranattPP, AkulaSM, ZienCA, KrishnanHH, ChandranB (2003) Kaposi's Sarcoma-Associated Herpesvirus Induces the Phosphatidylinositol 3-Kinase-PKC- -MEK-ERK Signaling Pathway in Target Cells Early during Infection: Implications for Infectivity. Journal of Virology 77: 1524–1539 doi:10.1128/JVI.77.2.1524-1539.2003

11. CiufoDM, CannonJS, PooleLJ, WuFY, MurrayP, et al. (2001) Spindle cell conversion by Kaposi's sarcoma-associated herpesvirus: formation of colonies and plaques with mixed lytic and latent gene expression in infected primary dermal microvascular endothelial cell cultures. Journal of Virology 75: 5614–5626 doi:10.1128/JVI.75.12.5614-5626.2001

12. McCormickC (2005) The Kaposin B Protein of KSHV Activates the p38/MK2 Pathway and Stabilizes Cytokine mRNAs. Science 307: 739–741 doi:10.1126/science.1105779

13. WinzenR, KrachtM, RitterB, WilhelmA, ChenCY, et al. (1999) The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. The EMBO Journal 18: 4969–4980 doi:10.1093/emboj/18.18.4969

14. NeiningerA, KontoyiannisD, KotlyarovA, WinzenR, EckertR, et al. (2002) MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. Journal of Biological Chemistry 277: 3065–3068 doi:10.1074/jbc.C100685200

15. ChenCY, ShyuAB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends in Biochemical Sciences 20: 465–470.

16. BakheetT, WilliamsBRG, KhabarKSA (2006) ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Research 34: D111–D114 doi:10.1093/nar/gkj052

17. SandujaS, BlancoFF, DixonDA (2010) The roles of TTP and BRF proteins in regulated mRNA decay. WIREs RNA 2: 42–57 doi:10.1002/wrna.28

18. YooJ, KangJ, LeeHN, AguilarB, KafkaD, et al. (2010) Kaposin-B Enhances the PROX1 mRNA Stability during Lymphatic Reprogramming of Vascular Endothelial Cells by Kaposi's Sarcoma Herpes Virus. PLoS Pathog 6: e1001046 doi:10.1371/journal.ppat.1001046

19. ParkerR, ShethU (2007) P Bodies and the Control of mRNA Translation and Degradation. Molecular Cell 25: 635–646 doi:10.1016/j.molcel.2007.02.011

20. Fenger-GrønM, FillmanC, NorrildB, Lykke-AndersenJ (2005) Multiple Processing Body Factors and the ARE Binding Protein TTP Activate mRNA Decapping. Molecular Cell 20: 905–915 doi:10.1016/j.molcel.2005.10.031

21. StoecklinG, MayoT, AndersonP (2006) ARE-mRNA degradation requires the 5′-3′ decay pathway. EMBO Rep 7: 72–77 doi:10.1038/sj.embor.7400572

22. Lykke-AndersenJ (2005) Recruitment and activation of mRNA decay enzymes by two ARE-mediated decay activation domains in the proteins TTP and BRF-1. Genes & Development 19: 351–361 doi:10.1101/gad.1282305

23. FranksTM, Lykke-AndersenJ (2007) TTP and BRF proteins nucleate processing body formation to silence mRNAs with AU-rich elements. Genes & Development 21: 719–735 doi:10.1101/gad.1494707

24. KedershaN, StoecklinG, AyodeleM, YaconoP, Lykke-AndersenJ, et al. (2005) Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. The Journal of Cell Biology 169: 871–884 doi:10.1083/jcb.200502088

25. EulalioA, Behm-AnsmantI, IzaurraldeE (2007) P bodies: at the crossroads of post-transcriptional pathways. Nat Rev Mol Cell Biol 8: 9–22 doi:10.1038/nrm2080

26. BrenguesM, TeixeiraD, ParkerR (2005) Movement of eukaryotic mRNAs between polysomes and cytoplasmic processing bodies. Science 310: 486–489 doi:10.1126/science.1115791

27. BhattacharyyaSN, HabermacherR, MartineU, ClossEI, FilipowiczW (2006) Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125: 1111–1124 doi:10.1016/j.cell.2006.04.031

28. KulkarniM, OzgurS, StoecklinG (2010) On track with P-bodies. Biochem Soc Trans 38: 242 doi:10.1042/BST0380242

29. AizerA, BrodyY, LerLW, SonenbergN, SingerRH, et al. (2008) The Dynamics of Mammalian P Body Transport, Assembly, and Disassembly In Vivo. Molecular Biology of the Cell 19: 4154–4166 doi:10.1091/mbc.E08

30. RajgorD, MelladJA, SoongD, RattnerJB, FritzlerMJ, et al. (2014) Mammalian microtubule P-body dynamics are mediated by nesprin-1. The Journal of Cell Biology 205: 457–475 doi:10.1083/jcb.201306076

31. LoschiM, LeishmanCC, BerardoneN, BoccaccioGL (2009) Dynein and kinesin regulate stress-granule and P-body dynamics. Journal of Cell Science 122: 3973–3982 doi:10.1242/jcs.051383

32. TakahashiS, SakuraiK, EbiharaA, KajihoH, SaitoK, et al. (2011) RhoA activation participates in rearrangement of processing bodies and release of nucleated AU-rich mRNAs. Nucleic Acids Research 39: 3446–3457 doi:10.1093/nar/gkq1302

33. SchmitzA (2000) Rho GTPases: Signaling, Migration, and Invasion. Experimental Cell Research 261: 1–12 doi:10.1006/excr.2000.5049

34. BuchsbaumRJ (2007) Rho activation at a glance. Journal of Cell Science 120: 1149–1152 doi:10.1242/jcs.03428

35. HallA (1998) Rho GTPases and the actin cytoskeleton. Science 279: 509–514.

36. HallA (2009) The cytoskeleton and cancer. Cancer Metastasis Rev 28: 5–14 doi:10.1007/s10555-008-9166-3

37. RidleyAJ (2001) Rho GTPases and cell migration. Journal of Cell Science 114: 2713–2722.

38. FujiharaH, WalkerLA, GongMC, LemichezE, BoquetP, et al. (1997) Inhibition of RhoA translocation and calcium sensitization by in vivo ADP-ribosylation with the chimeric toxin DC3B. molecular biology of the cell 8: 2437–2447.

39. SiehlerS (2009) Regulation of RhoGEF proteins by G 12/13-coupled receptors. British Journal of Pharmacology 158: 41–49 doi:10.1111/j.1476-5381.2009.00121.x

40. DubashAD, WennerbergK, Garcia-MataR, MenoldMM, ArthurWT, et al. (2007) A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin. Journal of Cell Science 120: 3989–3998 doi:10.1242/jcs.003806

41. BryanBA, D'AmorePA (2007) What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol Life Sci 64: 2053–2065 doi:10.1007/s00018-007-7008-z

42. MongPY, WangQ (2009) Activation of Rho Kinase Isoforms in Lung Endothelial Cells during Inflammation. The Journal of Immunology 182: 2385–2394 doi:10.4049/jimmunol.0802811

43. SomlyoAP, SomlyoAV (2000) Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol (Lond) 522 Pt 2: 177–185.

44. OhashiK, NagataK, MaekawaM, IshizakiT, NarumiyaS, et al. (2000) Rho-associated Kinase ROCK Activates LIM-kinase 1 by Phosphorylation at Threonine 508 within the Activation Loop*. Journal of Biological Chemistry 275: 3577–3582.

45. SumiT, MatsumotoK, TakaiY, NakamuraT (1999) Cofilin Phosphorylation and Actin Cytoskeletal Dynamics Regulated by Rho- and Cdc42-activated LIM-kinase 2. The Journal of Cell Biology 147: 1519–1532.

46. KotlyarovA, GaestelM (2002) Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? Biochem Soc Trans 30: 959–963.

47. KotlyarovA, YannoniY, FritzS, LaassK, TelliezJ-B, et al. (2002) Distinct cellular functions of MK2. Molecular and Cellular Biology 22: 4827–4835.

48. LandryJ, HuotJ (1999) Regulation of actin dynamics by stress-activated protein kinase 2 (SAPK2)-dependent phosphorylation of heat-shock protein of 27 kDa (Hsp27). Biochem Soc Symp 64: 79–89.

49. RousseauS, HouleF, HuotJ (2000) Integrating the VEGF signals leading to actin-based motility in vascular endothelial cells. Trends in Cardiovascular Medicine 10: 321–327.

50. LamaliceL, Le BoeufF, HuotJ (2007) Endothelial Cell Migration During Angiogenesis. Circulation Research 100: 782–794 doi:10.1161/01.RES.0000259593.07661.1e

51. GamellC, SusperreguiAG, BernardO, RosaJL, VenturaF (2011) The p38/MK2/Hsp25 Pathway Is Required for BMP-2-Induced Cell Migration. PLoS ONE 6: e16477 doi:10.1371/journal.pone.0016477

52. XuL, ChenS, BerganRC (2006) MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 25: 2987–2998 doi:10.1038/sj.onc.1209337

53. CoteMC, LavoieJR, HouleF, PoirierA, RousseauS, et al. (2010) Regulation of Vascular Endothelial Growth Factor-induced Endothelial Cell Migration by LIM Kinase 1-mediated Phosphorylation of Annexin 1. Journal of Biological Chemistry 285: 8013–8021 doi:10.1074/jbc.M109.098665

54. RogallaT, EhrnspergerM, PrevilleX, KotlyarovA, LutschG, et al. (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. Journal of Biological Chemistry 274: 18947–18956.

55. HuangJ, XieL-D, LuoL, ZhengS-L, WangH-J, et al. (2014) Silencing heat shock protein 27 (HSP27) inhibits the proliferation and migration of vascular smooth muscle cells in vitro. Mol Cell Biochem 390: 115–121 doi:10.1007/s11010-014-1962-1

56. KobayashiM, NishitaM, MishimaT, OhashiK, MizunoK (2006) MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. The EMBO Journal 25: 713–726 doi:10.1038/sj.emboj.7600973

57. AmanoM (1997) Formation of Actin Stress Fibers and Focal Adhesions Enhanced by Rho-Kinase. Science 275: 1308–1311 doi:10.1126/science.275.5304.1308

58. MaekawaM (1999) Signaling from Rho to the Actin Cytoskeleton Through Protein Kinases ROCK and LIM-kinase. Science 285: 895–898 doi:10.1126/science.285.5429.895

59. KayyaliUS (2002) Cytoskeletal Changes in Hypoxic Pulmonary Endothelial Cells Are Dependent on MAPK-activated Protein Kinase MK2. Journal of Biological Chemistry 277: 42596–42602 doi:10.1074/jbc.M205863200

60. RousseauS, HouleF, KotanidesH, WitteL, WaltenbergerJ, et al. (2000) Vascular endothelial growth factor (VEGF)-driven actin-based motility is mediated by VEGFR2 and requires concerted activation of stress-activated protein kinase 2 (SAPK2/p38) and geldanamycin-sensitive phosphorylation of focal adhesion kinase. Journal of Biological Chemistry 275: 10661–10672.

61. RousseauS, HouleF, LandryJ, HuotJ (1997) p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15: 2169–2177 doi:10.1038/sj.onc.1201380

62. AndersonDR, MeyersMJ, VernierWF, MahoneyMW, KurumbailRG, et al. (2007) Pyrrolopyridine Inhibitors of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK-2). J Med Chem 50: 2647–2654 doi:10.1021/jm0611004

63. GarciaMC, RayDM, LackfordB, RubinoM, OldenK, et al. (2009) Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27. Journal of Biological Chemistry 284: 20936–20945 doi:10.1074/jbc.M109.020271

64. Wittchen ES, Burridge K (2008) Chapter 14 Analysis of Low Molecular Weight GTPase Activity in Endothelial Cell Cultures. Angiogenesis - In Vitro Systems. Methods in Enzymology. Elsevier, Vol. 443. pp. 285–298. doi:10.1016/S0076-6879(08)02014-4.

65. YamadaT, OhokaY, KogoM, InagakiS (2005) Physical and Functional Interactions of the Lysophosphatidic Acid Receptors with PDZ Domain-containing Rho Guanine Nucleotide Exchange Factors (RhoGEFs). Journal of Biological Chemistry 280: 19358–19363 doi:10.1074/jbc.M414561200

66. ArandaE, OwenGI (2009) A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. Biological Research 42: 377–389.

67. CorcoranJA, KhaperskyyDA, JohnstonBP, KingCA, CyrDP, et al. (2012) Kaposi's Sarcoma-Associated Herpesvirus G-Protein-Coupled Receptor Prevents AU-Rich-Element-Mediated mRNA Decay. Journal of Virology 86: 8859–8871 doi:10.1128/JVI.00597-12

68. CougotN, CavalierA, ThomasD, GilletR (2012) The Dual Organization of P-bodies Revealed by Immunoelectron Microscopy and Electron Tomography. Journal of Molecular Biology 420: 17–28 doi:10.1016/j.jmb.2012.03.027

69. KrendelM, ZenkeFT, BokochGM (2002) Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol 4: 294–301 doi:10.1038/ncb773

70. FeigLA (1999) Tools of the trade: use of dominant-inhibitory mutants of Ras-family GTPases. Nat Cell Biol 1: E25–E27 doi:10.1038/10018

71. WildeC, AktoriesK (2001) The Rho-ADP-ribosylating C3 exoenzyme from Clostridiumbotulinum and related C3-like transferases. Toxicology 39: 1647–1660.

72. CorcoranJA, KhaperskyyDA, McCormickC (2011) Assays for monitoring viral manipulation of host ARE-mRNA turnover. Methods 55: 172–181 doi:10.1016/j.ymeth.2011.08.005

73. HittiE, IakovlevaT, BrookM, DeppenmeierS, GruberAD, et al. (2006) Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Molecular and Cellular Biology 26: 2399–2407 doi:10.1128/MCB.26.6.2399-2407.2006

74. KnapinskaAM, GratacosFM, KrauseCD, HernandezK, JensenAG, et al. (2011) Chaperone Hsp27 Modulates AUF1 Proteolysis and AU-Rich Element-Mediated mRNA Degradation. Molecular and Cellular Biology 31: 1419–1431 doi:10.1128/MCB.00907-10

75. ReinekeLC, LloydRE (2013) Diversion of stress granules and P-bodies during viral infection. Virology 436: 255–267 doi:10.1016/j.virol.2012.11.017

76. WardAM, BidetK, YinglinA, LerSG, HogueK, et al. (2011) Quantitative mass spectrometry of DENV-2 RNA-interacting proteins reveals that the DEAD-box RNA helicase DDX6 binds the DB1 and DB2 3′ UTR structures. RNA Biology 8: 1173–1186 doi:10.4161/rna.8.6.17836

77. NathansR, ChuC-Y, SerquinaAK, LuC-C, CaoH, et al. (2009) Cellular microRNA and P bodies modulate host-HIV-1 interactions. Molecular Cell 34: 696–709 doi:10.1016/j.molcel.2009.06.003

78. PijlmanGP, FunkA, KondratievaN, LeungJ, TorresS, et al. (2008) A highly structured, nuclease-resistant, noncoding RNA produced by flaviviruses is required for pathogenicity. Cell Host and Microbe 4: 579–591 doi:10.1016/j.chom.2008.10.007

79. ChaharHS, ChenS, ManjunathN (2013) P-body components LSM1, GW182, DDX3, DDX6 and XRN1 are recruited to WNV replication sites and positively regulate viral replication. Virology 436: 1–7 doi:10.1016/j.virol.2012.09.041

80. PagerCT, SchützS, AbrahamTM, LuoG, SarnowP (2013) Modulation of hepatitis C virus RNA abundance and virus release by dispersion of processing bodies and enrichment of stress granules. Virology 435: 472–484 doi:10.1016/j.virol.2012.10.027

81. ReedJC, MolterB, GearyCD, McNevinJ, McElrathJ, et al. (2012) HIV-1 Gag co-opts a cellular complex containing DDX6, a helicase that facilitates capsid assembly. The Journal of Cell Biology 198: 439–456 doi:10.1083/jcb.201111012

82. SetoE, InoueT, NakataniY, YamadaM, IsomuraH (2014) Processing bodies accumulate in human cytomegalovirus-infected cells and do not affect viral replication at high multiplicity of infection. Virology 458–459: 151–161 doi:10.1016/j.virol.2014.04.022

83. SweetTJ, BoyerB, HuW, BakerKE, CollerJ (2007) Microtubule disruption stimulates P-body formation. RNA 13: 493–502 doi:10.1261/rna.355807

84. IshizakiT, MorishimaY, OkamotoM, FuruyashikiT, KatoT, et al. (2001) Coordination of microtubules and the actin cytoskeleton by the Rho effector mDia1. Nat Cell Biol 3: 8–14 doi:10.1038/35050598

85. PalazzoAF, CookTA, AlbertsAS, GundersenGG (2001) mDia mediates Rho-regulated formation and orientation of stable microtubules. Nat Cell Biol 3: 723–729 doi:10.1038/35087035

86. StoecklinG, StubbsT, KedershaN, WaxS, RigbyWFC, et al. (2004) MK2-induced tristetraprolin: 14-3-3 complexes prevent stress granule association and ARE-mRNA decay. The EMBO Journal 23: 1313–1324 doi:10.1038/sj.emboj.7600163

87. YooS-M, AhnA-K, SeoT, HongHB, ChungM-A, et al. (2008) Centrifugal enhancement of Kaposi's sarcoma-associated virus infection of human endothelial cells in vitro. Journal of Virological Methods 154: 160–166 doi:10.1016/j.jviromet.2008.07.026

88. BruloisKF, ChangH, LeeAS-Y, EnsserA, WongL-Y, et al. (2012) Construction and manipulation of a new Kaposi's sarcoma-associated herpesvirus bacterial artificial chromosome clone. Journal of Virology 86: 9708–9720 doi:10.1128/JVI.01019-12