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Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1

Oncogene volume 38, pages 4340–4351 (2019)Cite this article

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Abstract

Kaposi’s sarcoma (KS)-associated herpesvirus (KSHV), a gamma-2 herpesvirus, is the causative agent of KS, primary effusion lymphoma (PEL), and a plasma cell variant of multicentric Castleman’s disease. Although KSHV latency is detected in KS-related tumors, oncogenic pathways activated by KSHV latent infection are not fully understood. Here, we found that retrotransposition of long interspersed element-1 (L1), a retrotransposon in the human genome, was enhanced in PEL cells. Among the KSHV latent genes, viral FLICE-inhibitory protein (vFLIP) enhanced L1 retrotransposition in an NF-κB-dependent manner. Intracellular cell adhesion molecule-1 (ICAM-1), an NF-κB target, regulated the vFLIP-mediated enhancement of L1 retrotransposition. Furthermore, ICAM-1 downregulated the expression of Moloney leukemia virus 10 (MOV10), an L1 restriction factor. Knockdown of ICAM-1 or overexpression of MOV10 relieved the vFLIP-mediated enhancement of L1 retrotransposition. Collectively, during KSHV latency, vFLIP upregulates ICAM-1 in an NF-κB-dependent manner, which, in turn, downregulates MOV10 expression and thereby enhances L1 retrotransposition. Because active L1 retrotransposition can lead to genomic instability, which is commonly found in KS and PEL, activation of L1 retrotransposition during KSHV latency may accelerate oncogenic processes through enhancing genomic instability. Our results suggest that L1 retrotransposition may be a novel target for impeding tumor development in KSHV-infected patients.

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References

  1. 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;266:1865–9.

    Article  CAS  Google Scholar 

  2. Dupin N, Gorin I, Deleuze J, Agut H, Huraux JM, Escande JP. Herpes-like DNA sequences, AIDS-related tumors, and Castleman’s disease. N Engl J Med. 1995;333:798. author reply798-9

    CAS  PubMed  Google Scholar 

  3. Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and those without HIV infection. N Engl J Med. 1995;332:1181–5.

    Article  CAS  Google Scholar 

  4. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi’s sarcoma–associated herpesvirus-like DNA sequences in AIDS-related body-cavity–based lymphomas. N Engl J Med. 1995;332:1186–91.

    Article  CAS  Google Scholar 

  5. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D, Babinet P, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86:1276–80.

    CAS  PubMed  Google Scholar 

  6. Boshoff C, Chang Y. Kaposi’s sarcoma-associated herpesvirus: a new DNA tumor virus. Annu Rev Med. 2001;52:453–70.

    Article  CAS  Google Scholar 

  7. Katano H, Sato Y, Kurata T, Mori S, Sata T. Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi’s sarcoma, and multicentric Castleman’s disease. Virology. 2000;269:335–44.

    Article  CAS  Google Scholar 

  8. Parravicini C, Chandran B, Corbellino M, Berti E, Paulli M, Moore PS, et al. Differential viral protein expression in Kaposi’s sarcoma-associated herpesvirus-infected diseases. Am J Pathol. 2000;156:743–9.

    Article  CAS  Google Scholar 

  9. Staudt MR, Dittmer DP. Viral latent proteins as targets for Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) induced lymphoma. Curr Drug Targets Infect Disord. 2003;3:129–35.

    Article  CAS  Google Scholar 

  10. Djerbi M, Screpanti V, Catrina AI, Bogen B, Biberfeld P, Grandien A. The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors. J Exp Med. 1999;190:1025–32.

    Article  CAS  Google Scholar 

  11. Sun Q, Matta H, Lu G, Chaudhary PM. Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-κB activation. Oncogene. 2006;25:2717–26.

    Article  CAS  Google Scholar 

  12. Sun Q, Zachariah S, Chaudhary PM. The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation. J Biol Chem. 2003;278:52437–45.

    Article  CAS  Google Scholar 

  13. Chaudhary PM, Jasmin A, Eby MT, Hood L. Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene. 1999;18:5738–46.

    Article  CAS  Google Scholar 

  14. 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;101:9399–404.

    Article  CAS  Google Scholar 

  15. Matta H, Sun Q, Moses G, Chaudhary PM. Molecular genetic analysis of human herpes virus 8-encoded viral FLICE inhibitory protein-induced NF-kappaB activation. J Biol Chem. 2003;278:52406–11.

    Article  CAS  Google Scholar 

  16. Goodier JL, Kazazian HH. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell. 2008;135:23–35.

    Article  CAS  Google Scholar 

  17. Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM, Eichler EE, et al. LINE-1 retrotransposition activity in human genomes. Cell. 2010;141:1159–70.

    Article  CAS  Google Scholar 

  18. Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA. 2003;100:5280–5.

    Article  CAS  Google Scholar 

  19. Dombroski BA, Mathias SL, Nanthakumar E, Scott AF, Kazazian HH. Isolation of an active human transposable element. Science. 1991;254:1805–8.

    Article  CAS  Google Scholar 

  20. Cost GJ, Feng Q, Jacquier A, Boeke JD. Human L1 element target-primed reverse transcription in vitro. EMBO J. 2002;21:5899–910.

    Article  CAS  Google Scholar 

  21. Burwinkel B, Kilimann MW. Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. J Mol Biol. 1998;277:513–7.

    Article  CAS  Google Scholar 

  22. Chen J-M, Stenson PD, Cooper DN, Férec C. A systematic analysis of LINE-1 endonuclease-dependent retrotranspositional events causing human genetic disease. Hum Genet. 2005;117:411–27.

    Article  CAS  Google Scholar 

  23. Belancio VP, Deininger PL, Roy-Engel AM. LINE dancing in the human genome: transposable elements and disease. Genome Med. 2009;1:97.

    Article  Google Scholar 

  24. Hancks DC, Kazazian HH. Active human retrotransposons: variation and disease. Curr Opin Genet Dev. 2012;22:191–203.

    Article  CAS  Google Scholar 

  25. Kazazian HH, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature. 1988;332:164–6.

    Article  CAS  Google Scholar 

  26. Holmes SE, Dombroski BA, Krebs CM, Boehm CD, Kazazian HH. A new retrotransposable human L1 element from the LRE2 locus on chromosome 1q produces a chimaeric insertion. Nat Genet. 1994;7:143–8.

    Article  CAS  Google Scholar 

  27. Honda T. Links between Human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma. Front Chem. 2016;4:21.

    Article  Google Scholar 

  28. Honda T. Potential links between hepadnavirus and bornavirus sequences in the host genome and cancer. Front Microbiol. 2017;8:2537.

    Article  Google Scholar 

  29. Goodier JL. Retrotransposition in tumors and brains. Mob DNA. 2014;5:11.

    Article  Google Scholar 

  30. Shukla R, Upton KR, Muñoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, et al. Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell. 2013;153:101–11.

    Article  CAS  Google Scholar 

  31. Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992;52:643–5.

    CAS  PubMed  Google Scholar 

  32. Scott EC, Gardner EJ, Masood A, Chuang NT, Vertino PM, Devine SE. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 2016;26:745–55.

    Article  CAS  Google Scholar 

  33. Xie Y, Rosser JM, Thompson TL, Boeke JD, An W. Characterization of L1 retrotransposition with high-throughput dual-luciferase assays. Nucleic Acids Res. 2011;39:e16–e16.

    Article  Google Scholar 

  34. Denli AM, Narvaiza I, Kerman BE, Pena M, Benner C, Marchetto MCN, et al. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. Cell. 2015;163:583–93.

    Article  CAS  Google Scholar 

  35. Bagnéris C, Ageichik AV, Cronin N, Wallace B, Collins M, Boshoff C, et al. Crystal structure of a vFlip-IKKγ complex: insights into viral activation of the IKK signalosome. Mol Cell. 2008;30:620–31.

    Article  Google Scholar 

  36. Punj V, Matta H, Chaudhary PM. A computational profiling of changes in gene expression and transcription factors induced by vFLIP K13 in primary effusion lymphoma. PLoS ONE. 2012;7:e37498.

    Article  CAS  Google Scholar 

  37. Ehrlich ES, Chmura JC, Smith JC, Kalu NN, Hayward GS. KSHV RTA abolishes NFκB responsive gene expression during lytic reactivation by targeting vFLIP for degradation via the proteasome. PLoS ONE. 2014;9:e91359.

    Article  Google Scholar 

  38. Goodier JL. Restricting retrotransposons: a review. Mob DNA. 2016;7:16.

    Article  Google Scholar 

  39. Dai L, Huang Q, Boeke JD. Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition. BMC Biochem. 2011;12:18.

    Article  CAS  Google Scholar 

  40. Goodier JL, Cheung LE, Kazazian HH. MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. PLoS Genet. 2012;8:e1002941.

    Article  CAS  Google Scholar 

  41. Li X, Zhang J, Jia R, Cheng V, Xu X, Qiao W, et al. The MOV10 Helicase Inhibits LINE-1 Mobility. J Biol Chem. 2013;288:21148–60.

    Article  CAS  Google Scholar 

  42. Radkov SA, Kellam P, Boshoff C. The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targetsthe retinoblastoma–E2F pathway and with the oncogene Hras transformsprimary rat cells. Nat Med. 2000;6:1121–7.

    Article  CAS  Google Scholar 

  43. Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature. 1997;390:184–7.

    Article  CAS  Google Scholar 

  44. Coscoy L. Immune evasion by Kaposi’s sarcoma-associated herpesvirus. Nat Rev Immunol. 2007;7:391–401.

    Article  CAS  Google Scholar 

  45. 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  Google Scholar 

  46. Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest. 2010;120:939–49.

    Article  CAS  Google Scholar 

  47. Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe. 2014;15:266–82.

    Article  CAS  Google Scholar 

  48. Dittmer DP, Damania B. Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016;126:3165–75.

    Article  Google Scholar 

  49. Delli Bovi P, Donti E, Knowles DM, Friedman-Kien A, Luciw PA, Dina D, et al. Presence of chromosomal abnormalities and lack of AIDS retrovirus DNA sequences in AIDS-associated Kaposi’s sarcoma. Cancer Res. 1986;46:6333–8.

    CAS  PubMed  Google Scholar 

  50. Gaidano G, Pastore C, Gloghini A, Capello D, Tirelli U, Saglio G, et al. Microsatellite instability in KSHV/HHV-8 positive body-cavity-based lymphoma. Hum Pathol. 1997;28:748–50.

    Article  CAS  Google Scholar 

  51. Delabesse E, Oksenhendler E, Lebbé C, Vérola O, Varet B, Turhan AG. Molecular analysis of clonality in Kaposi’s sarcoma. J Clin Pathol. 1997;50:664–8.

    Article  CAS  Google Scholar 

  52. Gill PS, Tsai YC, Rao AP, Spruck CH, Zheng T, Harrington WA, et al. Evidence for multiclonality in multicentric Kaposi’s sarcoma. Proc Natl Acad Sci USA. 1998;95:8257–61.

    Article  CAS  Google Scholar 

  53. Singer T, McConnell MJ, Marchetto MCN, Coufal NG, Gage FH. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci. 2010;33:345–54.

    Article  CAS  Google Scholar 

  54. Dupuy AJ, Rogers LM, Kim J, Nannapaneni K, Starr TK, Liu P, et al. A modified sleeping beauty transposon system that can be used to model a wide variety of human cancers in mice. Cancer Res. 2009;69:8150–6.

    Article  CAS  Google Scholar 

  55. Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, et al. PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science. 2010;330:1104–7.

    Article  CAS  Google Scholar 

  56. Ding D, Lou X, Hua D, Yu W, Li L, Wang J, et al. Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach. PLoS Genet. 2012;8:e1003065.

    Article  CAS  Google Scholar 

  57. Lau C-C, Sun T, Ching AKK, He M, Li J-W, Wong AM, et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell. 2014;25:335–49.

    Article  CAS  Google Scholar 

  58. Burns KH, Boeke JD. Human transposon tectonics. Cell. 2012;149:740–52.

    Article  CAS  Google Scholar 

  59. Ehrlich M. DNA methylation in cancer: too much, but also too little. Oncogene. 2002;21:5400–13.

    Article  CAS  Google Scholar 

  60. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002;418:646–50.

    Article  CAS  Google Scholar 

  61. Jaenisch R, Jähner D, Nobis P, Simon I, Löhler J, Harbers K, et al. Chromosomal position and activation of retroviral genomes inserted into the germ line of mice. Cell. 1981;24:519–29.

    Article  CAS  Google Scholar 

  62. Mooslehner K, Müller U, Karls U, Hamann L, Harbers K. Structure and expression of a gene encoding a putative GTP-binding protein identified by provirus integration in a transgenic mouse strain. Mol Cell Biol. 1991;11:886–93.

    Article  CAS  Google Scholar 

  63. Choi J, Hwang S-Y, Ahn K. Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition. Nucleic Acids Res. 2018;46:1912–26.

    Article  CAS  Google Scholar 

  64. Lawson C, Wolf S. ICAM-1 signaling in endothelial cells. Pharmacol Rep. 2009;61:22–32.

    Article  CAS  Google Scholar 

  65. Muro S, Wiewrodt R, Thomas A, Koniaris L, Albelda SM, Muzykantov VR, et al. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. J Cell Sci. 2003;116:1599–609.

    Article  CAS  Google Scholar 

  66. Holland J, Owens T. Signaling through intercellular adhesion molecule 1 (ICAM-1) in a B cell lymphoma line. The activation of Lyn tyrosine kinase and the mitogen-activated protein kinase pathway. J Biol Chem. 1997;272:9108–12.

    Article  CAS  Google Scholar 

  67. Adamson P, Etienne S, Couraud PO, Calder V, Greenwood J. Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a rho-dependent pathway. J Immunol. 1999;162:2964–73.

    CAS  PubMed  Google Scholar 

  68. Nishikawa Y, Nakayama R, Obika S, Ohsaki E, Ueda K, Honda T. Inhibition of LINE-1 retrotransposition by capsaicin. Int J Mol Sci. 2018;19:3243.

    Article  Google Scholar 

  69. Kinomoto M, Kanno T, Shimura M, Ishizaka Y, Kojima A, Kurata T, et al. All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. Nucleic Acids Res. 2007;35:2955–64.

    Article  CAS  Google Scholar 

  70. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, et al. L1 retrotransposition in human neural progenitor cells. Nature. 2009;460:1127–31.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by the MEXT/JSPS KAKENHI Grant Numbers 15K08496, 18H02664, and 18K19449 (T.H.), and grants from the Takeda Science Foundation, Senri Life Science Foundation, Suzuken Memorial Foundation, The Shimizu Foundation for Immunology and Neuroscience Grant for 2015, and The NOVARTIS Foundation (Japan) for the Promotion of Science (T.H.).

Author contributions

R.N., Y.U., and T.H. conducted the experiments; R.N., Y.U., K.U., and T. H. analyzed the data; T.H. conceived, designed the study, and wrote the paper.

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  1. Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka, Japan

    Ryota Nakayama, Yumiko Ueno, Keiji Ueda & Tomoyuki Honda

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  1. Ryota Nakayama
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Nakayama, R., Ueno, Y., Ueda, K. et al. Latent infection with Kaposi’s sarcoma-associated herpesvirus enhances retrotransposition of long interspersed element-1. Oncogene 38, 4340–4351 (2019). https://doi.org/10.1038/s41388-019-0726-5

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