1887

Abstract

Cervical cancer is one of the leading causes of death in women worldwide and is etiologically linked to human papillomavirus (HPV) infection. Viral early proteins E6 and E7 manipulate cellular functions to promote the virus life cycle and are essential to the cellular transformation process. The innate immune system plays a pivotal role in the natural history of HPV infection. Among the various proteins that mediate the innate immune response, Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and initiate the immune response. The objective of this study was to identify HPV E6 protein interaction partners in the TLR signalling pathway that may play a role in the immune response against HPV. Six TLR pathway proteins were shown to interact with HPV16 E6: myeloid differentiation primary response protein (MyD88), TIR domain-containing adapter molecule 1 (TRIF), interleukin-1 receptor-associated kinase-like (IRAK) 2, TNF receptor-associated factor (TRAF) 6, I-κB kinase beta (IKKβ) and I-κB kinase epsilon (IKKε). The interaction site of IKKε with E6 is located in the region containing the enzyme catalytic site, suggesting an influence of E6 on the activation of IKKε target proteins. HPV16 E6 potentiated the activation of NF-κB by various TLR pathway members. These results suggest that HPV16 has the ability to interfere with components of the immune response, contributing to HPV carcinogenesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001057
2018-03-29
2019-09-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/99/5/667.html?itemId=/content/journal/jgv/10.1099/jgv.0.001057&mimeType=html&fmt=ahah

References

  1. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11: 373– 384 [CrossRef] [PubMed]
    [Google Scholar]
  2. O'Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors - redefining innate immunity. Nat Rev Immunol 2013; 13: 453– 460 [CrossRef] [PubMed]
    [Google Scholar]
  3. Joosten LA, Abdollahi-Roodsaz S, Dinarello CA, O'Neill L, Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol 2016; 12: 344– 357 [CrossRef] [PubMed]
    [Google Scholar]
  4. Bruni L, Barrionuevo-Rosas L, Albero G, Serrano B, Mena M et al. Human Papillomavirus and Related Diseases in the World: ICO Information Centre on HPV and Cancer (HPV Information Centre) Summary Report 27 July 2017 2017
    [Google Scholar]
  5. Schlecht NF, Kulaga S, Robitaille J, Ferreira S, Santos M et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 2001; 286: 3106– 3114 [CrossRef] [PubMed]
    [Google Scholar]
  6. Stanley M. Immune responses to human papillomavirus. Vaccine 2006; 24: S16– S22 [CrossRef] [PubMed]
    [Google Scholar]
  7. Amador-Molina A, Hernández-Valencia JF, Lamoyi E, Contreras-Paredes A, Lizano M. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses 2013; 5: 2624– 2642 [CrossRef] [PubMed]
    [Google Scholar]
  8. Koshiol J, Kovacic MB. Cytokines and markers of immune response to HPV infection. Inflammation and Infections 2012
    [Google Scholar]
  9. McMurray HR, Nguyen D, Westbrook TF, McAnce DJ. Biology of human papillomaviruses. Int J Exp Pathol 2001; 82: 15– 33 [CrossRef] [PubMed]
    [Google Scholar]
  10. Howie HL, Katzenellenbogen RA, Galloway DA. Papillomavirus E6 proteins. Virology 2009; 384: 324– 334 [CrossRef] [PubMed]
    [Google Scholar]
  11. vande Pol SB, Klingelhutz AJ. Papillomavirus E6 oncoproteins. Virology 2013; 445: 115– 137 [CrossRef] [PubMed]
    [Google Scholar]
  12. Zanier K, Charbonnier S, Sidi AO, McEwen AG, Ferrario MG et al. Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science 2013; 339: 694– 698 [CrossRef] [PubMed]
    [Google Scholar]
  13. Lebre MC, van der Aar AM, van Baarsen L, van Capel TM, Schuitemaker JH et al. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. J Invest Dermatol 2007; 127: 331– 341 [CrossRef] [PubMed]
    [Google Scholar]
  14. Nasu K, Narahara H. Pattern recognition via the toll-like receptor system in the human female genital tract. Mediators Inflamm 2010; 2010: 1– 12 [CrossRef] [PubMed]
    [Google Scholar]
  15. Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R et al. TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. J Immunol 2007; 178: 3186– 3197 [CrossRef] [PubMed]
    [Google Scholar]
  16. Hasan UA, Zannetti C, Parroche P, Goutagny N, Malfroy M et al. The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. J Exp Med 2013; 210: 1369– 1387 [CrossRef] [PubMed]
    [Google Scholar]
  17. Daud II, Scott ME, Ma Y, Shiboski S, Farhat S et al. Association between toll-like receptor expression and human papillomavirus type 16 persistence. Int J Cancer 2011; 128: 879– 886 [CrossRef] [PubMed]
    [Google Scholar]
  18. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 2008; 105: 652– 656 [CrossRef] [PubMed]
    [Google Scholar]
  19. Kfoury A, Virard F, Renno T, Coste I. Dual function of MyD88 in inflammation and oncogenesis: implications for therapeutic intervention. Curr Opin Oncol 2014; 26: 86– 91 [CrossRef] [PubMed]
    [Google Scholar]
  20. Salcedo R, Cataisson C, Hasan U, Yuspa SH, Trinchieri G. MyD88 and its divergent toll in carcinogenesis. Trends Immunol 2013; 34: 379– 389 [CrossRef] [PubMed]
    [Google Scholar]
  21. Boccardo E, Lepique AP, Villa LL. The role of inflammation in HPV carcinogenesis. Carcinogenesis 2010; 31: 1905– 1912 [CrossRef] [PubMed]
    [Google Scholar]
  22. Peters RT, Liao SM, Maniatis T. IKKepsilon is part of a novel PMA-inducible IkappaB kinase complex. Mol Cell 2000; 5: 513– 522 [CrossRef] [PubMed]
    [Google Scholar]
  23. Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 2007; 129: 1065– 1079 [CrossRef] [PubMed]
    [Google Scholar]
  24. Guo JP, Shu SK, Esposito NN, Coppola D, Koomen JM et al. IKKepsilon phosphorylation of estrogen receptor alpha Ser-167 and contribution to tamoxifen resistance in breast cancer. J Biol Chem 2010; 285: 3676– 3684 [CrossRef] [PubMed]
    [Google Scholar]
  25. Qin B, Cheng K. Silencing of the IKKε gene by siRNA inhibits invasiveness and growth of breast cancer cells. Breast Cancer Res 2010; 12: R74 [CrossRef] [PubMed]
    [Google Scholar]
  26. Hsu S, Kim M, Hernandez L, Grajales V, Noonan A et al. IKK-ε coordinates invasion and metastasis of ovarian cancer. Cancer Res 2012; 72: 5494– 5504 [CrossRef] [PubMed]
    [Google Scholar]
  27. Li H, Chen L, Zhang A, Wang G, Han L et al. Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo. Int J Oncol 2012; 41: 169– 178 [CrossRef] [PubMed]
    [Google Scholar]
  28. Renner F, Moreno R, Schmitz ML. SUMOylation-dependent localization of IKKepsilon in PML nuclear bodies is essential for protection against DNA-damage-triggered cell death. Mol Cell 2010; 37: 503– 515 [CrossRef] [PubMed]
    [Google Scholar]
  29. Verhelst K, Verstrepen L, Carpentier I, Beyaert R. IkappaB kinase epsilon (IKKepsilon): a therapeutic target in inflammation and cancer. Biochem Pharmacol 2013; 85: 873– 880 [Crossref]
    [Google Scholar]
  30. Kaukinen P, Sillanpää M, Nousiainen L, Melén K, Julkunen I. Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKε and TBK1 functions. J Med Virol 2013; 85: 71– 82 [CrossRef] [PubMed]
    [Google Scholar]
  31. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S et al. IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci USA 2013; 110: 11139– 11144 [CrossRef] [PubMed]
    [Google Scholar]
  32. Kim TY, Myoung HJ, Kim JH, Moon IS, Kim TG et al. Both E7 and CpG-oligodeoxynucleotide are required for protective immunity against challenge with human papillomavirus 16 (E6/E7) immortalized tumor cells: involvement of CD4+ and CD8+ T cells in protection. Cancer Res 2002; 62: 7234– 7240 [PubMed]
    [Google Scholar]
  33. Kim Y, Girardi M, Duvic M, Kuzel T, Rook A et al. TLR9 Agonist immunomodulator treatment of cutaneous T-cell lymphoma (CTCL) with CPG7909. Blood 2004; 104: 743
    [Google Scholar]
  34. Krieg AM. Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 2006; 5: 471– 484 [CrossRef] [PubMed]
    [Google Scholar]
  35. Fahey LM, Raff AB, da Silva DM, Kast WM. Reversal of human papillomavirus-specific T cell immune suppression through TLR agonist treatment of Langerhans cells exposed to human papillomavirus type 16. J Immunol 2009; 182: 2919– 2928 [CrossRef] [PubMed]
    [Google Scholar]
  36. Chen XZ, Mao XH, Zhu KJ, Jin N, Ye J et al. Toll like receptor agonists augment HPV 11 E7-specific T cell responses by modulating monocyte-derived dendritic cells. Arch Dermatol Res 2010; 302: 57– 65 [CrossRef] [PubMed]
    [Google Scholar]
  37. Stanley MA, Pett MR, Coleman N. HPV: from infection to cancer. Biochem Soc Trans 2007; 35: 1456– 1460 [CrossRef] [PubMed]
    [Google Scholar]
  38. Tindle RW. Immune evasion in human papillomavirus-associated cervical cancer. Nat Rev Cancer 2002; 2: 59– 64 [CrossRef] [PubMed]
    [Google Scholar]
  39. Tomaić V, Pim D, Banks L. The stability of the human papillomavirus E6 oncoprotein is E6AP dependent. Virology 2009; 393: 7– 10 [CrossRef] [PubMed]
    [Google Scholar]
  40. Ansari T, Brimer N, vande Pol SB. Peptide interactions stabilize and restructure human papillomavirus type 16 E6 to interact with p53. J Virol 2012; 86: 11386– 11391 [CrossRef] [PubMed]
    [Google Scholar]
  41. White EA, Kramer RE, Tan MJ, Hayes SD, Harper JW et al. Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J Virol 2012; 86: 13174– 13186 [CrossRef] [PubMed]
    [Google Scholar]
  42. UniProt Consortium UniProt: a hub for protein information. Nucleic Acids Res 2015; 43: [accessed 08/08/2016] [CrossRef] [PubMed]
    [Google Scholar]
  43. Dolganiuc A, Oak S, Kodys K, Golenbock DT, Finberg RW et al. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 2004; 127: 1513– 1524 [CrossRef] [PubMed]
    [Google Scholar]
  44. Boehme KW, Guerrero M, Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells. J Immunol 2006; 177: 7094– 7102 [CrossRef] [PubMed]
    [Google Scholar]
  45. Cai M, Li M, Wang K, Wang S, Lu Q et al. The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-κB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway. PLoS One 2013; 8: e54586 [CrossRef] [PubMed]
    [Google Scholar]
  46. Mesri EA, Feitelson MA, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 2014; 15: 266– 282 [CrossRef] [PubMed]
    [Google Scholar]
  47. Pandey S, Mittal RD, Srivastava M, Srivastava K, Singh S et al. Impact of Toll-like receptors [TLR] 2 (-196 to -174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women. Gynecol Oncol 2009; 114: 501– 505 [CrossRef] [PubMed]
    [Google Scholar]
  48. Clément JF, Meloche S, Servant MJ. The IKK-related kinases: from innate immunity to oncogenesis. Cell Res 2008; 18: 889– 899 [CrossRef] [PubMed]
    [Google Scholar]
  49. James MA, Lee JH, Klingelhutz AJ. Human papillomavirus type 16 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol 2006; 80: 5301– 5307 [CrossRef] [PubMed]
    [Google Scholar]
  50. Shen RR, Hahn WC. Emerging roles for the non-canonical IKKs in cancer. Oncogene 2011; 30: 631– 641 [CrossRef] [PubMed]
    [Google Scholar]
  51. Mine KL, Shulzhenko N, Yambartsev A, Rochman M, Sanson GF et al. Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer. Nat Commun 2013; 4: 4 [CrossRef] [PubMed]
    [Google Scholar]
  52. Vandermark ER, Deluca KA, Gardner CR, Marker DF, Schreiner CN et al. Human papillomavirus type 16 E6 and E 7 proteins alter NF-kB in cultured cervical epithelial cells and inhibition of NF-kB promotes cell growth and immortalization. Virology 2012; 425: 53– 60 [CrossRef] [PubMed]
    [Google Scholar]
  53. Ronco LV, Karpova AY, Vidal M, Howley PM. Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 1998; 12: 2061– 2072 [CrossRef] [PubMed]
    [Google Scholar]
  54. Boutell C, Everett RD. Regulation of alphaherpesvirus infections by the ICP0 family of proteins. J Gen Virol 2013; 94: 465– 481 [CrossRef] [PubMed]
    [Google Scholar]
  55. Hiscott J, Nguyen TL, Arguello M, Nakhaei P, Paz S. Manipulation of the nuclear factor-κB pathway and the innate immune response by viruses. Oncogene 2006; 25: 6844– 6867 [CrossRef] [PubMed]
    [Google Scholar]
  56. Melén K, Fagerlund R, Nyqvist M, Keskinen P, Julkunen I. Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. J Med Virol 2004; 73: 536– 547 [CrossRef] [PubMed]
    [Google Scholar]
  57. So EY, Ouchi T. The application of Toll like receptors for cancer therapy. Int J Biol Sci 2010; 6: 675– 681 [PubMed] [Crossref]
    [Google Scholar]
  58. Zhu J, Mohan C. Toll-like receptor signaling pathways-therapeutic opportunities. Mediators Inflamm 2010; 2010: 1– 7 [CrossRef] [PubMed]
    [Google Scholar]
  59. Ohlschläger P, Spies E, Alvarez G, Quetting M, Groettrup M. The combination of TLR-9 adjuvantation and electroporation-mediated delivery enhances in vivo antitumor responses after vaccination with HPV-16 E7 encoding DNA. Int J Cancer 2011; 128: 473– 481 [CrossRef] [PubMed]
    [Google Scholar]
  60. Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA et al. Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 2013; 73: 4791– 4800 [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001057
Loading
/content/journal/jgv/10.1099/jgv.0.001057
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error