CIB1 Synergizes with EphrinA2 to Regulate Kaposi's Sarcoma-Associated Herpesvirus Macropinocytic Entry in Human Microvascular Dermal Endothelial Cells

English version České info

KSHV envelope glycoproteins interact with cell surface heparan sulfate and integrins, and activate FAK, Src, PI3-K, c-Cbl, and Rho-GTPase signal molecules in human microvascular dermal endothelial (HMVEC-d) cells. c-Cbl mediates the translocation of virus bound α3β1 and αVβ3 integrins into lipid rafts (LRs), where KSHV interacts and activates EphrinA2 (EphA2). EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. To identify the factor(s) coordinating the EphA2-signal complex, the role of CIB1 (calcium and integrin binding protein-1) associated with integrin signaling was analyzed. CIB1 knockdown did not affect KSHV binding to HMVEC-d cells but significantly reduced its entry and gene expression. In contrast, CIB1 overexpression increased KSHV entry in 293 cells. Single virus particle infection and trafficking during HMVEC-d cell entry was examined by utilizing DiI (envelope) and BrdU (viral DNA) labeled virus. CIB1 was associated with KSHV in membrane blebs and in Rab5 positive macropinocytic vesicles. CIB1 knockdown abrogated virus induced blebs, macropinocytosis and virus association with the Rab5 macropinosome. Infection increased the association of CIB1 with LRs, and CIB1 was associated with EphA2 and KSHV entry associated signal molecules such as Src, PI3-K, and c-Cbl. CIB1 knockdown significantly reduced the infection induced EphA2, Src and Erk1/2 activation. Mass spectrometry revealed the simultaneous association of CIB1 and EphA2 with the actin cytoskeleton modulating myosin IIA and alpha-actinin 4 molecules, and CIB1 knockdown reduced EphA2's association with myosin IIA and alpha-actinin 4. Collectively, these studies revealed for the first time that CIB1 plays a role in virus entry and macropinocytosis, and suggested that KSHV utilizes CIB1 as one of the key molecule(s) to coordinate and sustain the EphA2 mediated signaling involved in its entry, and CIB1 is an attractive therapeutic target to block KSHV infection.

Vyšlo v časopise: CIB1 Synergizes with EphrinA2 to Regulate Kaposi's Sarcoma-Associated Herpesvirus Macropinocytic Entry in Human Microvascular Dermal Endothelial Cells. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003941
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003941

Souhrn

Zdroje

1. ChangY, CesarmanE, PessinMS, LeeF, CulpepperJ, et al. (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266: 1865–1869.

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.

3. Ganem D (2007) Kaposi's sarcoma-associated herpesvirus. Fields virology 5th ed., vol. 2: p. 2875–2888.

4. ChandranB Early events in Kaposi's sarcoma-associated herpesvirus infection of target cells. J Virol 84: 2188–2199.

5. ChakrabortyS, VeettilMV, ChandranB Kaposi's Sarcoma Associated Herpesvirus Entry into Target Cells. Front Microbiol 3: 6.

6. AkulaSM, PramodNP, WangFZ, ChandranB (2001) Human herpesvirus 8 envelope-associated glycoprotein B interacts with heparan sulfate-like moieties. Virology 284: 235–249.

7. WangFZ, AkulaSM, PramodNP, ZengL, ChandranB (2001) Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 75: 7517–7527.

8. BirkmannA, MahrK, EnsserA, YagubogluS, TitgemeyerF, et al. (2001) Cell surface heparan sulfate is a receptor for human herpesvirus 8 and interacts with envelope glycoprotein K8.1. J Virol 75: 11583–11593.

9. AkulaSM, WangFZ, VieiraJ, ChandranB (2001) Human herpesvirus 8 interaction with target cells involves heparan sulfate. Virology 282: 245–255.

10. WangFZ, AkulaSM, Sharma-WaliaN, ZengL, ChandranB (2003) Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol 77: 3131–3147.

11. HahnA, BirkmannA, WiesE, DorerD, MahrK, et al. (2009) Kaposi's sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. J Virol 83: 396–407.

12. NaranattPP, AkulaSM, ZienCA, KrishnanHH, ChandranB (2003) Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity. J Virol 77: 1524–1539.

13. VeettilMV, Sharma-WaliaN, SadagopanS, RaghuH, SivakumarR, et al. (2006) RhoA-GTPase facilitates entry of Kaposi's sarcoma-associated herpesvirus into adherent target cells in a Src-dependent manner. J Virol 80: 11432–11446.

14. VeettilMV, SadagopanS, Sharma-WaliaN, WangFZ, RaghuH, et al. (2008) Kaposi's sarcoma-associated herpesvirus forms a multimolecular complex of integrins (alphaVbeta5, alphaVbeta3, and alpha3beta1) and CD98-xCT during infection of human dermal microvascular endothelial cells, and CD98-xCT is essential for the postentry stage of infection. J Virol 82: 12126–12144.

15. RaghuH, Sharma-WaliaN, VeettilMV, SadagopanS, ChandranB (2009) Kaposi's sarcoma-associated herpesvirus utilizes an actin polymerization-dependent macropinocytic pathway to enter human dermal microvascular endothelial and human umbilical vein endothelial cells. J Virol 83: 4895–4911.

16. NaranattPP, KrishnanHH, SmithMS, ChandranB (2005) Kaposi's sarcoma-associated herpesvirus modulates microtubule dynamics via RhoA-GTP-diaphanous 2 signaling and utilizes the dynein motors to deliver its DNA to the nucleus. J Virol 79: 1191–1206.

17. KrishnanHH, Sharma-WaliaN, StreblowDN, NaranattPP, ChandranB (2006) Focal adhesion kinase is critical for entry of Kaposi's sarcoma-associated herpesvirus into target cells. J Virol 80: 1167–1180.

18. 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.

19. 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.

20. AkulaSM, NaranattPP, WaliaNS, WangFZ, FegleyB, et al. (2003) Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 77: 7978–7990.

21. Valiya VeettilM, SadagopanS, KerurN, ChakrabortyS, ChandranB Interaction of c-Cbl with myosin IIA regulates Bleb associated macropinocytosis of Kaposi's sarcoma-associated herpesvirus. PLoS Pathog 6: e1001238.

22. ChakrabortyS, ValiyaVeettilM, SadagopanS, PaudelN, ChandranB c-Cbl-mediated selective virus-receptor translocations into lipid rafts regulate productive Kaposi's sarcoma-associated herpesvirus infection in endothelial cells. J Virol 85: 12410–12430.

23. ChakrabortyS, VeettilMV, BotteroV, ChandranB (2012) Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc Natl Acad Sci U S A 109: E1163–1172.

24. HahnAS, KaufmannJK, WiesE, NaschbergerE, Panteleev-IvlevJ, et al. (2012) The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus. Nat Med 18: 961–966.

25. BoshoffC (2012) Ephrin receptor: a door to KSHV infection. Nat Med 18: 861–863.

26. DuttaD, ChakrabortyS, BandyopadhyayC, Valiya VeettilM, AnsariMA, et al. (2013) EphrinA2 regulates clathrin mediated KSHV endocytosis in fibroblast cells by coordinating integrin-associated signaling and c-Cbl directed polyubiquitination. PLoS Pathog 9: e1003510.

27. KerrMC, TeasdaleRD (2009) Defining macropinocytosis. Traffic 10: 364–371.

28. JonesAT (2007) Macropinocytosis: searching for an endocytic identity and role in the uptake of cell penetrating peptides. J Cell Mol Med 11: 670–684.

29. MarshM, HeleniusA (2006) Virus entry: open sesame. Cell 124: 729–740.

30. DikicI, SzymkiewiczI, SoubeyranP (2003) Cbl signaling networks in the regulation of cell function. Cell Mol Life Sci 60: 1805–1827.

31. YuanW, LeisnerTM, McFaddenAW, WangZ, LarsonMK, et al. (2006) CIB1 is an endogenous inhibitor of agonist-induced integrin alphaIIbbeta3 activation. J Cell Biol 172: 169–175.

32. NaikUP, PatelPM, PariseLV (1997) Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain. J Biol Chem 272: 4651–4654.

33. ShockDD, NaikUP, BrittainJE, AlahariSK, SondekJ, et al. (1999) Calcium-dependent properties of CIB binding to the integrin alphaIIb cytoplasmic domain and translocation to the platelet cytoskeleton. Biochem J 342 Pt 3: 729–735.

34. LeisnerTM, LiuM, JafferZM, ChernoffJ, PariseLV (2005) Essential role of CIB1 in regulating PAK1 activation and cell migration. J Cell Biol 170: 465–476.

35. NaikMU, PhamNT, BeebeK, DaiW, NaikUP (2011) Calcium-dependent inhibition of polo-like kinase 3 activity by CIB1 in breast cancer cells. Int J Cancer 128: 587–596.

36. KauselmannG, WeilerM, WulffP, JessbergerS, KonietzkoU, et al. (1999) The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. EMBO J 18: 5528–5539.

37. WhiteC, YangJ, MonteiroMJ, FoskettJK (2006) CIB1, a ubiquitously expressed Ca2+-binding protein ligand of the InsP3 receptor Ca2+ release channel. J Biol Chem 281: 20825–20833.

38. StablerSM, OstrowskiLL, JanickiSM, MonteiroMJ (1999) A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. J Cell Biol 145: 1277–1292.

39. HollenbachAD, McPhersonCJ, LagutinaI, GrosveldG (2002) The EF-hand calcium-binding protein calmyrin inhibits the transcriptional and DNA-binding activity of Pax3. Biochim Biophys Acta 1574: 321–328.

40. HaatajaL, KaartinenV, GroffenJ, HeisterkampN (2002) The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading. J Biol Chem 277: 8321–8328.

41. WuX, LieberMR (1997) Interaction between DNA-dependent protein kinase and a novel protein, KIP. Mutat Res 385: 13–20.

42. NaikMU, NaikUP (2003) Calcium-and integrin-binding protein regulates focal adhesion kinase activity during platelet spreading on immobilized fibrinogen. Blood 102: 3629–3636.

43. NaikMU, NaikUP (2011) Contra-regulation of calcium- and integrin-binding protein 1-induced cell migration on fibronectin by PAK1 and MAP kinase signaling. J Cell Biochem 112: 3289–3299.

44. GentryHR, SingerAU, BettsL, YangC, FerraraJD, et al. (2005) Structural and biochemical characterization of CIB1 delineates a new family of EF-hand-containing proteins. J Biol Chem 280: 8407–8415.

45. JarmanKE, MorettiPA, ZebolJR, PitsonSM (2010) Translocation of sphingosine kinase 1 to the plasma membrane is mediated by calcium- and integrin-binding protein 1. J Biol Chem 285: 483–492.

46. NaikUP, NaikMU (2003) Association of CIB with GPIIb/IIIa during outside-in signaling is required for platelet spreading on fibrinogen. Blood 102: 1355–1362.

47. KostyakJC, NaikMU, NaikUP (2012) Calcium- and integrin-binding protein 1 regulates megakaryocyte ploidy, adhesion, and migration. Blood 119: 838–846.

48. KakigiA, OkadaT, TakedaT, TakedaS, TaguchiD, et al. (2010) Endocytosis of MPO in marginal cells is regulated by PKC, protein phosphatase, ERK and PI3-K signaling cascades, but not by PKA and MEK signaling cascades. ORL J Otorhinolaryngol Relat Spec 72: 188–195.

49. MettlenM, PlatekA, Van Der SmissenP, CarpentierS, AmyereM, et al. (2006) Src triggers circular ruffling and macropinocytosis at the apical surface of polarized MDCK cells. Traffic 7: 589–603.

50. YorkRD, MolliverDC, GrewalSS, StenbergPE, McCleskeyEW, et al. (2000) Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1. Mol Cell Biol 20: 8069–8083.

51. Sharma-WaliaN, NaranattPP, KrishnanHH, ZengL, ChandranB (2004) Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 envelope glycoprotein gB induces the integrin-dependent focal adhesion kinase-Src-phosphatidylinositol 3-kinase-rho GTPase signal pathways and cytoskeletal rearrangements. J Virol 78: 4207–4223.

52. DonepudiM, ReshMD (2008) c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling. Cell Signal 20: 1359–1367.

53. AkulaSM, PramodNP, WangFZ, ChandranB (2002) Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108: 407–419.

54. 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.

55. JohnsonKE, ChikotiL, ChandranB (2013) Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87: 5005–5018.

56. VargheseS, RabkinSD, NielsenGP, MacGarveyU, LiuR, et al. (2007) Systemic therapy of spontaneous prostate cancer in transgenic mice with oncolytic herpes simplex viruses. Cancer Res 67: 9371–9379.

57. Le BlancI, LuyetPP, PonsV, FergusonC, EmansN, et al. (2005) Endosome-to-cytosol transport of viral nucleocapsids. Nat Cell Biol 7: 653–664.

58. ZhuFX, LiX, ZhouF, GaoSJ, YuanY (2006) Functional characterization of Kaposi's sarcoma-associated herpesvirus ORF45 by bacterial artificial chromosome-based mutagenesis. J Virol 80: 12187–12196.

59. SadagopanS, Sharma-WaliaN, VeettilMV, BotteroV, LevineR, et al. (2009) Kaposi's sarcoma-associated herpesvirus upregulates angiogenin during infection of human dermal microvascular endothelial cells, which induces 45S rRNA synthesis, antiapoptosis, cell proliferation, migration, and angiogenesis. J Virol 83: 3342–3364.

60. ZhuL, PuriV, ChandranB (1999) Characterization of human herpesvirus-8 K8.1A/B glycoproteins by monoclonal antibodies. Virology 262: 237–249.

61. KalamvokiM, RoizmanB (2010) Interwoven roles of cyclin D3 and cdk4 recruited by ICP0 and ICP4 in the expression of herpes simplex virus genes. J Virol 84: 9709–9717.

62. 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.

63. SongKS, LiS, OkamotoT, QuilliamLA, SargiacomoM, et al. (1996) Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J Biol Chem 271: 9690–9697.

64. 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.

65. FordPW, HamdenKE, WhitmanAG, McCubreyJA, AkulaSM (2004) Vascular endothelial growth factor augments human herpesvirus-8 (HHV-8/KSHV) infection. Cancer Biol Ther 3: 876–881.

66. George PaulA, Sharma-WaliaN, KerurN, WhiteC, ChandranB Piracy of prostaglandin E2/EP receptor-mediated signaling by Kaposi's sarcoma-associated herpes virus (HHV-8) for latency gene expression: strategy of a successful pathogen. Cancer Res 70: 3697–3708.

67. RappoccioloG, HenslerHR, JaisM, ReinhartTA, PeguA, et al. (2008) Human herpesvirus 8 infects and replicates in primary cultures of activated B lymphocytes through DC-SIGN. J Virol 82: 4793–4806.

68. LanzettiL, PalamidessiA, ArecesL, ScitaG, Di FiorePP (2004) Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases. Nature 429: 309–314.

69. TinevezJY, SchulzeU, SalbreuxG, RoenschJ, JoannyJF, et al. (2009) Role of cortical tension in bleb growth. Proc Natl Acad Sci U S A 106: 18581–18586.

70. FritzscheM, LewalleA, DukeT, KruseK, CharrasG (2013) Analysis of turnover dynamics of the submembranous actin cortex. Mol Biol Cell 24: 757–767.

71. MercerJ, HeleniusA (2012) Gulping rather than sipping: macropinocytosis as a way of virus entry. Curr Opin Microbiol 15: 490–499.

72. MercerJ, SchelhaasM, HeleniusA (2010) Virus entry by endocytosis. Annu Rev Biochem 79: 803–833.

73. GobeilLA, LodgeR, TremblayMJ (2013) Macropinocytosis-like HIV-1 internalization in macrophages is CCR5 dependent and leads to efficient but delayed degradation in endosomal compartments. J Virol 87: 735–745.

74. KriegerSE, KimC, ZhangL, MarjomakiV, BergelsonJM (2013) Echovirus 1 entry into polarized caco-2 cells depends on dynamin, cholesterol, and cellular factors associated with macropinocytosis. J Virol 87: 8884–8895.

75. CoyneCB, ShenL, TurnerJR, BergelsonJM (2007) Coxsackievirus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5. Cell Host Microbe 2: 181–192.

76. MercerJ, HeleniusA (2008) Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 320: 531–535.

77. BlazejczykM, SobczakA, DebowskaK, WisniewskaMB, KirilenkoA, et al. (2009) Biochemical characterization and expression analysis of a novel EF-hand Ca2+ binding protein calmyrin2 (Cib2) in brain indicates its function in NMDA receptor mediated Ca2+ signaling. Arch Biochem Biophys 487: 66–78.

78. HagerM, BigottiMG, MeszarosR, CarmignacV, HolmbergJ, et al. (2008) Cib2 binds integrin alpha7Bbeta1D and is reduced in laminin alpha2 chain-deficient muscular dystrophy. J Biol Chem 283: 24760–24769.

79. DashDP, SilvestriG, HughesAE (2006) Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis. Mol Vis 12: 499–505.

80. BinZ (2007) Regulation of cell survival by CIB1, a new modulator of phosphoinositide-dependent protein kinase-1 (PDK1). FASEB 6: LB12.

81. NguyenJT, TurckCW, CohenFE, ZuckermannRN, LimWA (1998) Exploiting the basis of proline recognition by SH3 and WW domains: design of N-substituted inhibitors. Science 282: 2088–2092.

82. WaksmanG, KominosD, RobertsonSC, PantN, BaltimoreD, et al. (1992) Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature 358: 646–653.

83. YeFC, ZhouFC, NithiananthamS, ChandranB, YuXL, et al. (2013) Kaposi's sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells. J Virol 87: 6326–6335.

84. CarterN, NakamotoT, HiraiH, HunterT (2002) EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nat Cell Biol 4: 565–573.

85. SalaitaK, GrovesJT (2010) Roles of the cytoskeleton in regulating EphA2 signals. Commun Integr Biol 3: 454–457.

86. TangN, LinT, YangJ, FoskettJK, OstapEM (2007) CIB1 and CaBP1 bind to the myo1c regulatory domain. J Muscle Res Cell Motil 28: 285–291.