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YGLF motif in the Kaposi sarcoma herpes virus G-protein-coupled receptor adjusts NF-κB activation and paracrine actions

Oncogene volume 33, pages 5609–5618 (2014)Cite this article

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Abstract

Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) are two pathologies associated with KS herpes virus (KSHV/HHV-8) infection. KSHV genome contains several oncogenes, among which, the viral G-protein-coupled receptor (vGPCR open reading frame 74) has emerged as a major factor in KS pathogenicity. Indeed, vGPCR is a constitutively active receptor, whose expression is sufficient to drive cell transformation in vitro and tumour development in mice. However, neither the role of vGPCR in KSHV-infected B-lymphocytes nor the molecular basis for its constitutive activation is well understood. Here, we show that vGPCR expression contributes to nuclear factor-κB (NF-κB)-dependent cellular survival in both PEL cells and primary B cells from HIV-negative KS patients. We further identified within vGPCR an AP2 consensus binding motif, Y326GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y326A) increased NF-κB activity and proinflammatory cytokines production. This correlated with exacerbated morphological rearrangement, migration and proliferation of non-infected monocytes. Collectively, our work raises the possibility that KSHV-infected B-lymphocytes use vGPCR to impact ultimately the immune response and communication within the tumour microenvironment in KSHV-associated pathologies.

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References

  1. Lanternier F, Lebbe C, Schartz N, Farhi D, Marcelin AG, Kerob D et al. Kaposi's sarcoma in HIV-negative men having sex with men. AIDS 2008; 22: 1163–1168.

    Article  CAS  PubMed  Google Scholar 

  2. Lodi S, Guiguet M, Costagliola D, Fisher M, de Luca A, Porter K . Kaposi sarcoma incidence and survival among HIV-infected homosexual men after HIV seroconversion. J Natl Cancer Inst 2010; 102: 784–792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mesri EA, Cesarman E, Boshoff C . Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 2010; 10: 707–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 1994; 266: 1865–1869.

    Article  CAS  PubMed  Google Scholar 

  5. Boshoff C, Whitby D, Hatziioannou T, Fisher C, van der Walt J, Hatzakis A et al. Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma. Lancet 1995; 345: 1043–1044.

    Article  CAS  PubMed  Google Scholar 

  6. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C et al. Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV-infected individuals and progression to Kaposi's sarcoma. Lancet 1995; 346: 799–802.

    Article  CAS  PubMed  Google Scholar 

  7. Cesarman E, Nador RG, Aozasa K, Delsol G, Said JW, Knowles DM . Kaposi's sarcoma-associated herpesvirus in non-AIDS related lymphomas occurring in body cavities. Am J Pathol 1996; 149: 53–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mesri EA, Cesarman E, Arvanitakis L, Rafii S, Moore MA, Posnett DN et al. Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new transmissible virus that infects B cells. J Exp Med 1996; 183: 2385–2390.

    Article  CAS  PubMed  Google Scholar 

  9. Chen YB, Rahemtullah A, Hochberg E . Primary effusion lymphoma. Oncologist 2007; 12: 569–576.

    Article  PubMed  Google Scholar 

  10. An J, Sun Y, Fisher M, Rettig MB . Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 2004; 18: 1699–1704.

    Article  CAS  PubMed  Google Scholar 

  11. Matta H, Chaudhary PM . Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci USA 2004; 101: 9399–9404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Keller SA, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, Schattner EJ et al. NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 2006; 107: 3295–3302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Montaner S, Sodhi A, Servitja JM, Ramsdell AK, Barac A, Sawai ET et al. The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 2004; 104: 2903–2911.

    Article  CAS  PubMed  Google Scholar 

  14. Grossmann C, Podgrabinska S, Skobe M, Ganem D . Activation of NF-kappaB 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. J Virol 2006; 80: 7179–7185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Caselli E, Fiorentini S, Amici C, Di Luca D, Caruso A, Santoro MG . Human herpesvirus 8 acute infection of endothelial cells induces monocyte chemoattractant protein 1-dependent capillary-like structure formation: role of the IKK/NF-kappaB pathway. Blood 2007; 109: 2718–2726.

    CAS  PubMed  Google Scholar 

  16. Martin D, Galisteo R, Ji Y, Montaner S, Gutkind JS . An NF-kappaB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene 2008; 27: 1844–1852.

    Article  CAS  PubMed  Google Scholar 

  17. Guasparri I, Keller SA, Cesarman E . KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 2004; 199: 993–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu L, Eby MT, Rathore N, Sinha SK, Kumar A, Chaudhary PM . The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem 2002; 277: 13745–13751.

    Article  CAS  PubMed  Google Scholar 

  19. Field N, Low W, Daniels M, Howell S, Daviet L, Boshoff C et al. KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci 2003; 116 (Part 18): 3721–3728.

    Article  CAS  PubMed  Google Scholar 

  20. Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 2003; 3: 23–36.

    Article  CAS  PubMed  Google Scholar 

  21. Chugh P, Matta H, Schamus S, Zachariah S, Kumar A, Richardson JA et al. Constitutive NF-kappaB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice. Proc Natl Acad Sci USA 2005; 102: 12885–12890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ballon G, Chen K, Perez R, Tam W, Cesarman E . Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice. J Clin Invest 2011; 121: 1141–1153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Boshoff C . Unraveling virus-induced lymphomagenesis. J Clin Invest 2011; 121: 838–841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sin SH, Dittmer DP . Viral latency locus augments B cell response in vivo to induce chronic marginal zone enlargement, plasma cell hyperplasia and lymphoma. Blood 2013; 121: 2952–2963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E . Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997; 385: 347–350.

    Article  CAS  PubMed  Google Scholar 

  26. Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 1998; 391: 86–89.

    Article  CAS  PubMed  Google Scholar 

  27. Rosenkilde MM, Kledal TN, Holst PJ, Schwartz TW . Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74. J Biol Chem 2000; 275: 26309–26315.

    Article  CAS  PubMed  Google Scholar 

  28. Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J Exp Med 2000; 191: 445–454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bais C, Van Geelen A, Eroles P, Mutlu A, Chiozzini C, Dias S et al. Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR. Cancer Cell 2003; 3: 131–143.

    Article  CAS  PubMed  Google Scholar 

  30. Martin D, Galisteo R, Molinolo AA, Wetzker R, Hirsch E, Gutkind JS . PI3Kgamma mediates Kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 2011; 19: 805–813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Couty JP, Geras-Raaka E, Weksler BB, Gershengorn MC . Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. J Biol Chem 2001; 276: 33805–33811.

    Article  CAS  PubMed  Google Scholar 

  32. Smit MJ, Verzijl D, Casarosa P, Navis M, Timmerman H, Leurs R . Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via G(i) and phospholipase C-dependent signaling pathways. J Virol 2002; 76: 1744–1752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dwyer J, Le Guelte A, Galan Moya EM, Sumbal M, Carlotti A, Douguet L et al. Remodeling of VE-cadherin junctions by the human herpes virus 8G-protein coupled receptor. Oncogene 2011; 30: 190–200.

    Article  CAS  PubMed  Google Scholar 

  34. Schwarz M, Murphy PM . Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-kappa B and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol 2001; 167: 505–513.

    Article  CAS  PubMed  Google Scholar 

  35. Cannon M, Philpott NJ, Cesarman E . The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J Virol 2003; 77: 57–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lagos D, Vart RJ, Gratrix F, Westrop SJ, Emuss V, Wong PP et al. Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe 2008; 4: 470–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Montaner S, Kufareva I, Abagyan R, Gutkind JS . Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Annu Rev Pharmacol Toxicol 2013; 53: 331–354.

    Article  CAS  PubMed  Google Scholar 

  38. de Oliveira DE, Ballon G, Cesarman E . NF-kappaB signaling modulation by EBV and KSHV. Trends Microbiol 2010; 18: 248–257.

    Article  CAS  PubMed  Google Scholar 

  39. Chang HH, Ganem D . A unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 2013; 13: 429–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu F, Xia Y, Parker AS, Verma IM . IKK biology. Immunol Rev. 2012; 246: 239–253.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Marchese A, Chen C, Kim YM, Benovic JL . The ins and outs of G protein-coupled receptor trafficking. Trends Biochem Sci 2003; 28: 369–376.

    Article  CAS  PubMed  Google Scholar 

  42. Waugh DJJ, Wilson C . The interleukin-8 pathway in cancer. Clin Cancer Res 2008; 14: 6735–6741.

    Article  CAS  PubMed  Google Scholar 

  43. Hassman LM, Ellison TJ, Kedes DH . KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. J Clin Invest 2011; 121: 752–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Myoung J, Ganem D . Active lytic infection of human primary tonsillar B cells by KSHV and its noncytolytic control by activated CD4+ T cells. J Clin Invest 2011; 121: 1130–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cannon ML, Cesarman E . The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene 2004; 23: 514–523.

    Article  CAS  PubMed  Google Scholar 

  46. Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA et al. Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor. Proc Natl Acad Sci USA 2004; 101: 4821–4826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Benmerah A, Bayrou M, Cerf-Bensussan N, Dautry-Varsat A . Inhibition of clathrin-coated pit assembly by an Eps15 mutant. J Cell Sci 1999; 112 (Part 9): 1303–1311.

    CAS  PubMed  Google Scholar 

  48. Dwyer J, Hebda JK, Le Guelte A, Galan-Moya EM, Smith SS, Azzi S et al. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2. PLoS One 2012; 7: e45562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tan W, Martin D, Gutkind JS . The Galpha13-Rho signaling axis is required for SDF-1-induced migration through CXCR4. J Biol Chem 2006; 281: 39542–39549.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the members of JG laboratory for comments on the manuscript. We are grateful to Dr A Benmerah (Institut Necker, Paris, France) for the EPS15 constructs and helpful discussion and to C Catherinet (INSA, Rennes, France) for technical support. This research was funded by: ANR JCJC, Fondation ARC, Fondation pour la Recherche Medicale, INCA_6508, Ligue nationale contre le cancer comite de Paris and a Marie Curie International Reintegration Grant within The Seventh Framework Program. SA, SSS and JD are supported by postdoctoral fellowships from Fondation ARC, Canceropole Ile-de-France and ANRS, respectively. JKH is supported by a doctoral fellowship from Universite Paris Descartes.

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  1. S Azzi and S S Smith: These authors equally contributed to this work.

Authors and Affiliations

  1. CNRS, UMR8104, Paris, France

    S Azzi, S S Smith, J Dwyer, H M Leclair, J K Hebda & J Gavard

  2. INSERM, U1016, Paris, France

    S Azzi, S S Smith, J Dwyer, H M Leclair, J K Hebda & J Gavard

  3. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France

    S Azzi, S S Smith, J Dwyer, H M Leclair, J K Hebda, N Dupin & J Gavard

  4. INSERM, U1014, Hopital Paul Brousse, Villejuif, France

    C Alexia & N Bidère

  5. Universite Paris-Sud P11, Orsay, France

    C Alexia & N Bidère

  6. Equipe Labellisee Ligue contre le Cancer, Villejuif, France

    C Alexia & N Bidère

  7. Service de dermatologie, Hopital Cochin-Tarnier, AP-HP, Paris, France

    N Dupin

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Correspondence to J Gavard.

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SA performed experiments, analysed data and drafted the manuscript; SSS performed experiments, analysed data and drafted the manuscript; JD performed experiments, analysed data and drafted the manuscript; HML performed experiments; CA performed experiments and analysed data; JKH performed experiments; ND collected clinical samples; NB analysed data and drafted the manuscript; JG designed research, performed experiments, analysed data and wrote the manuscript.

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Azzi, S., Smith, S., Dwyer, J. et al. YGLF motif in the Kaposi sarcoma herpes virus G-protein-coupled receptor adjusts NF-κB activation and paracrine actions. Oncogene 33, 5609–5618 (2014). https://doi.org/10.1038/onc.2013.503

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