Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells

Oncogene volume 27, pages 1071–1078 (2008)Cite this article

A Corrigendum to this article was published on 23 October 2008

Abstract

High-risk human papillomaviruses (HPVs), especially HPV-16, play a primary role in the pathogenesis of cervical cancer. HPV-16 encodes the E5, E6 and E7 oncoproteins. Although the biological functions of E5 are poorly understood, recent studies indicate that its expression correlates with papillomavirus oncogenicity. In this study we demonstrate that the HPV-16 E5 oncoprotein increases plasma membrane expression of caveolin-1, which is a constituent of lipid rafts and regulator of cell signaling, and that this phenotype is mediated by the C-terminal 10 amino acids of E5. Moreover, E5 (but not mutant E5) induces a 23- to 40-fold increase in the lipid raft component, ganglioside GM1, on the cell surface and mediates a dramatic increase in caveolin-1/GM1 association. Since gangliosides strongly inhibit cytotoxic T lymphocytes, block immune synapse formation and are expressed at high levels on the surface of many tumor cells, our results suggest a potential mechanism for immune evasion by the papillomaviruses. Additionally, surface gangliosides are known to enhance proliferative signaling by the epidermal growth factor (EGF) receptor, providing a possible mechanistic basis for observations that EGF signaling is enhanced in E5-expressing cells. Finally, the upregulation of caveolin-1 and ganglioside GM1 at the plasma membrane of E5-expressing cervical cells provides potential new therapeutic targets and diagnostic markers for high-risk HPV infections.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Ashrafi GH, Haghshenas M, Marchetti B, Campo MS . (2006). E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Int J Cancer 119: 2105–2112.

    Article  CAS  PubMed  Google Scholar 

  • Bacia K, Scherfeld D, Kahya N, Schwille P . (2004). Fluorescence correlation spectroscopy relates rafts in model and native membranes. Biophys J 87: 1034–1043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baege AC, Berger A, Schlegel R, Veldman T, Schlegel R . (2002). Cervical epithelial cells transduced with the papillomavirus E6/E7 oncogenes maintain stable levels of oncoprotein expression but exhibit progressive, major increases in hTERT gene expression and telomerase activity. Am J Pathol 160: 1251–1257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bravo IG, Crusius K, Alonso A . (2005). The E5 protein of the human papillomavirus type 16 modulates composition and dynamics of membrane lipids in keratinocytes. Arch Virol 150: 231–246.

    Article  CAS  PubMed  Google Scholar 

  • Brown DA, London E . (1998). Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14: 111–136.

    Article  CAS  PubMed  Google Scholar 

  • Cebo C, Da Rocha S, Wittnebel S, Turhan AG, Abdelali J, Caillat-Zucman S et al. (2006). The decreased susceptibility of Bcr/Abl targets to NK cell-mediated lysis in response to imatinib mesylate involves modulation of NKG2D ligands, GM1 expression and synapse formation. J Immunol 176: 864–872.

    Article  CAS  PubMed  Google Scholar 

  • Chamberlain LH . (2004). Detergents as tools for the purification and classification of lipid rafts. FEBS Lett 559: 1–5.

    Article  CAS  PubMed  Google Scholar 

  • Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S . (2003). Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 88: 63–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Conrad M, Bubb VJ, Schlegel R . (1993). The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein. J Virol 67: 6170–6178.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Davis DM, Dustin ML . (2004). What is the importance of the immunological synapse? Trends Immunol 25: 323–327.

    Article  CAS  PubMed  Google Scholar 

  • Denker SP, McCaffery JM, Palade GE, Insel PA, Farquhar MG . (1996). Differential distribution of α subunits and βγ subunits of heterotrimeric G proteins on Golgi membranes of the exocrine pancreas. J Cell Biol 133: 1027–1040.

    Article  CAS  PubMed  Google Scholar 

  • Disbrow GL, Hanover JA, Schlegel R . (2005). Endoplasmic reticulum-localized human papillomavirus type 16 E5 protein alters endosomal pH but not trans-Golgi pH. J Virol 79: 5839–5846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Disbrow GL, Sunitha I, Baker CC, Hanover J, Schlegel R . (2003). Codon optimization of the HPV-16 E5 gene enhances protein expression. Virology 311: 105–114.

    Article  CAS  PubMed  Google Scholar 

  • Fehrmann F, Laimins LA . (2003). Human papillomaviruses: targeting differentiating cells for malignant transformation. Oncogene 22: 5201–5207.

    Article  CAS  PubMed  Google Scholar 

  • Fra AM, Masserini M, Palestini P, Sonnino S, Simons K . (1995). A photo-reactive derivative of ganglioside GM1 specifically cross-links VIP21-caveolin on the cell surface. FEBS Lett 375: 11–14.

    Article  CAS  PubMed  Google Scholar 

  • Frazer IH . (1996). Immunology of papillomavirus infection. Curr Opin Immunol 8: 484–491.

    Article  CAS  PubMed  Google Scholar 

  • Genther-Williams SM, Disbrow GL, Schlegel R, Lee D, Threadgill DW, Lambert PF . (2005). Requirement of epidermal growth factor receptor for hyperplasia induced by E5, a high-risk human papillomavirus oncogene. Cancer Res 65: 6534–6542.

    Article  CAS  PubMed  Google Scholar 

  • Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM et al. (1999). The immunological synapse: a molecular machine controlling T cell activation. Science 285: 221–227.

    Article  CAS  PubMed  Google Scholar 

  • Hansson GC, Simons K, van Meer G . (1986). Two strains of the Madin Darby canine kidney (MDCK) cell line have distinct glycosphingolipid compositions. EMBO J 5: 483–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hao M, Mukherjee S, Sun Y, Maxfield FR . (2004). Effects of cholesterol depletion and increased lipid unsaturation on the properties of endocytic membranes. J Biol Chem 279: 14171–14178.

    Article  CAS  PubMed  Google Scholar 

  • McKallip R, Li R, Ladisch S . (1999). Tumor gangliosides inhibit the tumor-specific immune response. J Immunol 163: 3718–3726.

    CAS  PubMed  Google Scholar 

  • Mundy DI, Machleidt T, Ying Y, Anderson RGW, Bloom GS . (2002). Dual control of caveolar membrane traffic by microtubules and the actin cytoskeleton. J Cell Sci 115: 4327–4339.

    Article  CAS  PubMed  Google Scholar 

  • Nishio M, Tajima O, Furukawa K, Urano T, Furukawa K . (2005). Over-expression of GM1 enhances cell proliferation with epidermal growth factor without affecting the receptor localization in the microdomain in PC12 cells. Int J Oncol 26: 191–199.

    CAS  PubMed  Google Scholar 

  • O’Brien PM, Campo MS . (2002). Evasion of host immunity directed by papillomavirus-encoded proteins. Virus Res 88: 103–117.

    Article  PubMed  Google Scholar 

  • Parton RG . (1994). Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem 42: 155–166.

    Article  CAS  PubMed  Google Scholar 

  • Razani B, Woodman SE, Lisanti MP . (2002). Caveolae: from cell biology to animal physiology. Pharmacol Rev 54: 431–467.

    Article  CAS  PubMed  Google Scholar 

  • Riley RR, Duensing S, Brake T, Munger K, Lambert PF, Arbeit JM . (2003). Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res 63: 4862–4871.

    CAS  PubMed  Google Scholar 

  • Rodriguez MI, Finbow ME, Alonso A . (2000). Binding of human papillomavirus 16 E5 to the 16 kDa subunit c (proteolipid) of the vacuolar H+-ATPase can be dissociated from the E5-mediated epidermal growth factor receptor overactivation. Oncogene 19: 3727–3732.

    Article  CAS  PubMed  Google Scholar 

  • Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC et al. (2005). The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 337: 76–84.

    Article  CAS  PubMed  Google Scholar 

  • Shurin GV, Shurin MR, Bykovskaia S, Shogan J, Lotze MT, Barksdale EM . (2001). Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61: 363–369.

    CAS  PubMed  Google Scholar 

  • Skibbens JE, Roth MG, Matlin KS . (1989). Differential extractability of influenza virus hemagglutinin during intracellular transport in polarized epithelial cells and nonpolar fibroblasts. J Cell Biol 108: 821–832.

    Article  CAS  PubMed  Google Scholar 

  • Sotgia F, Razani B, Bonuccelli G, Schubert W, Battista M, Lee H et al. (2002). Intracellular retention of glycosylphosphatidyl inositol-linked proteins in caveolin-deficient cells. Mol Cell Biol 22: 3905–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stuermer CA, Lang DM, Kirsch F, Wiechers M, Deininger SO, Plattner H . (2001). Glycosylphosphatidyl inositol-anchored proteins and fyn kinase assemble in noncaveolar plasma membrane microdomains defined by reggie-1 and -2. Mol Biol Cell 12: 3031–3045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suprynowicz FA, Campo MS, Schlegel R . (2006). Biological activities of papillomavirus E5 proteins. In: Campo MS (ed). Papillomavirus Research: From Natural History to Vaccines and Beyond. Caister Academic Press: Wymondham, UK, pp 97–113.

    Google Scholar 

  • Suprynowicz FA, Disbrow GL, Simic V, Schlegel R . (2005). Are transforming properties of the bovine papillomavirus E5 protein shared by E5 from high-risk human papillomavirus type 16? Virology 332: 102–113.

    Article  CAS  PubMed  Google Scholar 

  • Thomsen P, Roepstorff K, Stahlhut M, van Deurs B . (2002). Caveolae are highly immobile plasma membrane microdomains, which are not involved in constitutive endocytic trafficking. Mol Biol Cell 13: 238–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomsen P, van Deurs B, Norrild B, Kayser L . (2000). The HPV-16 E5 oncogene inhibits endocytic trafficking. Oncogene 19: 6023–6032.

    Article  CAS  PubMed  Google Scholar 

  • van Meer G . (1989). Lipid traffic in animal cells. Annu Rev Cell Biol 5: 247–275.

    Article  CAS  PubMed  Google Scholar 

  • Vyas YM, Maniar H, Dupont B . (2002). Visualization of signaling pathways and cortical cytoskeleton in cytolytic and noncytolytic natural killer cell immune synapses. Immunol Rev 189: 161–178.

    Article  CAS  PubMed  Google Scholar 

  • Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV et al. (1999). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189: 12–19.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grant R01-CA053371 from the National Cancer Institute (to RS).

Author information

Authors and Affiliations

  1. Department of Pathology, Georgetown University Medical School, Washington, DC, USA

    F A Suprynowicz, G L Disbrow, E Krawczyk, V Simic, K Lantzky & R Schlegel

Authors
  1. F A Suprynowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G L Disbrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Krawczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Simic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Lantzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Schlegel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Schlegel.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suprynowicz, F., Disbrow, G., Krawczyk, E. et al. HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells. Oncogene 27, 1071–1078 (2008). https://doi.org/10.1038/sj.onc.1210725

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210725

Keywords

This article is cited by

Search

Advanced search

Quick links