Skip to main content

Insights into the role and function of L2, the minor capsid protein of papillomaviruses

Abstract

Human papillomaviruses (HPV) are responsible for the most common human sexually transmitted viral infections, and high-risk types are responsible for causing cervical and other cancers. The minor capsid protein L2 of HPV plays important roles in virus entry into cells, localisation of viral components to the nucleus, in DNA binding, capsid formation and stability. It also elicits antibodies that are more cross-reactive between HPV types than does the major capsid protein L1, making it an attractive potential target for new-generation, more broadly protective subunit vaccines against HPV infections. However, its low abundance in natural capsids—12–72 molecules per 360 copies of L1—limits its immunogenicity. This review will explore the biological roles of the protein, and prospects for its use in new vaccines.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Alphs H, Gambhira R, Karanam B, Roberts JN, Jagu S, Schiller JT, Zeng W, Jackson DC, Roden RBS (2008) Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2. Proc Natl Acad Sci USA 15:5850–5855

    Article  Google Scholar 

  2. Becker KA, Florin L, Sapp C, Maul GG, Sapp M (2004) Nuclear localization but not PML protein is required for incorporation of the papillomavirus minor capsid protein L2 into the virus-like particles. Virology 78:1121–1128

    CAS  Article  Google Scholar 

  3. Bossis I, Roden RBS, Gambhira R, Yang R, Tagaya M, Howley PM, Meneses PI (2005) Interaction of tSNARE syntaxin 18 with the papillomavirus minor capsid protein mediates infection. J Virol 79:6723–6731

    PubMed  CAS  Article  Google Scholar 

  4. Bousarghin L, Touzé A, Combita-Rojas A, Coursaget P (2003) Positively charged sequence of human papillomavirus type 16 capsid proteins are sufficient to mediate gene transfer into target cells via the heparan sulphate receptor. J Gen Virol 84:157–164

    PubMed  CAS  Article  Google Scholar 

  5. Brown DR, Fife KH, Wheeler CM, Koutsky LA, Lupinacci L, Railkar R, Suhr G, Barr E, Dicello A, Li W, Smith JF, Tadesse A, Jansen KU (2004) Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine. Vaccine 22:2936–2942

    PubMed  CAS  Article  Google Scholar 

  6. Buck CB, Cheng N, Thompson CD, Lowy D, Steven AC, Schiller JT, Trus BL (2008) Arrangement of L2 within the papillomavirus capsid. J Virol 82:5190–5197

    PubMed  CAS  Article  Google Scholar 

  7. Buck CB, Thompson CD, Pang Y-YS, Lowy D, Schiller JT (2005) Maturation of papillomavirus capsids. J Virol 79:2839–2846

    PubMed  CAS  Article  Google Scholar 

  8. Carter J, Wipf GC, Madeleine MM, Schwartz S, Koutsky LA, Galloway DA (2006) Identification of human papillomavirus type 16 L1 surface loops required for neutralization by human sera. J Virol 80:4664–4672

    PubMed  CAS  Article  Google Scholar 

  9. Casini G, Graham D, Heine D, Garcea RL, Wu DT (2004) In vitro papillomavirus capsid assembly analyzed by light scattering. Virology 325:320–327

    PubMed  CAS  Article  Google Scholar 

  10. Chan JK, Berek JS (2007) Impact of the human papilloma vaccine on cervical cancer. J Clin Oncol 25:2975–2982

    PubMed  CAS  Article  Google Scholar 

  11. Chen XS, Garcea RL, Goldberg I, Casini G, Harrison SC (2000) Structure of small virus-like particles assembled from the L1 protein of human papillomavirus 16. Mol Cell 5:557–567

    PubMed  CAS  Article  Google Scholar 

  12. Christensen ND, Dillner J, Eklund C, Carter J, Wipf GC, Reed CA, Cladel NM, Galloway DA (1996) Surface conformational and linear epitopes on the HPV-16 and HPV-18 L1 virus-like particles as defined by monclonal antibodies. Virology 223:174–184

    PubMed  CAS  Article  Google Scholar 

  13. Conway M, Meyers C (2007) Genetic analysis of HPV-16 L2 conserved cysteines and cross-neutralization of synthetic vs authentic virions. PS25-01, international papillomavirus society and Chinese medical association, 24th international papillomavirus conference, Beijing

  14. Culp TD, Budgeon LR, Marinkovich MP, Meneguzzi G, Christensen ND (2006) Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells. J Virol 80:8940–8950

    PubMed  CAS  Article  Google Scholar 

  15. Day PM, Baker CC, Lowy DR, Schiller JT (2004) Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression. Proc Natl Acad Sci USA 101:14252–14257

    PubMed  CAS  Article  Google Scholar 

  16. Day PM, Gambhira R, Roden RB, Lowy DR, Schiller JT (2008) Mechanisms of human papillomavirus type 16 neutralization by l2 cross-neutralizing and l1 type-specific antibodies. J Virol 82:4638–4646

    PubMed  CAS  Article  Google Scholar 

  17. Day PM, Lowy DR, Schiller JT (2008) Heparan sulfate-independent cell binding and infection with furin-precleaved papillomavirus capsids. J Virol 82:12565–12568

    PubMed  CAS  Article  Google Scholar 

  18. Day PM, Thompson CD, Buck CB, Pang Y-YS, Lowy D, Schiller JT (2007) Neutralization of human papillomavirus with monoclonal antibodies reveals different mechanisms of inhibition. J Virol 81:8784–8792

    PubMed  CAS  Article  Google Scholar 

  19. de Villiers E-M, Fauquet C, Broker TR, Bernard H-M, zur Hausen H (2004) Classification of papillomaviruses. Virology 324:17–27

    PubMed  Article  CAS  Google Scholar 

  20. Fay A, Yutzy WH, Roden RB, Moroianu J (2004) The positively charged termini of L2 minor capsid protein required for bovine papillomavirus infection function separately in nuclear import and DNA binding. J Virol 78:13447–13454

    PubMed  CAS  Article  Google Scholar 

  21. Finnen RL, Erikson KD, Chen XS, Garcea RL (2003) Interactions between papillomavirus L1 and L2 capsid proteins. J Virol 77:4818–4826

    PubMed  CAS  Article  Google Scholar 

  22. Florin L, Becker KA, Lambert C, Nowak T, Sapp C, Strand D, Streek RE, Sapp M (2006) Identification of a dynein interacting domain in the papillomavirus minor capsid protein L2. J Virol 80:6691–6696

    PubMed  CAS  Article  Google Scholar 

  23. Florin L, Schafer K, Sotlar K, Streek RE, Sapp M (2002) Reorganization of nuclear domain 10 induced by the papillomavirus capsid protein L2. Virology 295:97–107

    PubMed  CAS  Article  Google Scholar 

  24. Gambhira R, Jagu S, Karanam B, Gravitt PE, Culp TD, Christensen ND, Roden RBS (2007) Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2. J Virol 81:11585–11592

    PubMed  CAS  Article  Google Scholar 

  25. Gambhira R, Karanam B, Jagu S, Roberts JN, Buck CB, Bossis I, Alphs H, Culp TD, Christensen ND, Roden RBS (2007) A protective and broadly cross-neutralizing epitope of human papillomavirus L2. J Virol 81:13927–13931

    PubMed  CAS  Article  Google Scholar 

  26. Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RI, Thun MJ (2007) Global cancer facts and figures 2007. American Cancer Society, Atlanta

    Google Scholar 

  27. Goldie SJ, Kohli M, Grima D, Weinstein MC, Wright TC, Bosch FX, Franco EL (2004) Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine. J Natl Cancer Inst 96:604–615

    PubMed  Article  Google Scholar 

  28. Görnemann J, Hofmann TG, Will T, Müller M (2002) Interaction of human papillomavirus type 16 L2 with cellular proteins: identification of novel nuclear body-associated proteins. Virology 303:69–78

    PubMed  Article  Google Scholar 

  29. Hagensee ME, Yaegashi N, Galloway DA (1993) Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of L1 and L2 capsid proteins. J Virol 67:315–322

    PubMed  CAS  Google Scholar 

  30. Heino P, Zhou J, Lambert PF (2000) Interaction of the papillomavirus transcription/replication factor, E2, and the viral capsid protein, L2. Virology 276:304–314

    PubMed  CAS  Article  Google Scholar 

  31. Holmgren SC, Patterson NA, Ozbun MA, Lambert PF (2005) The minor capsid protein L2 contributes to two steps in the human papillomavirus type 31 life cycle. J Virol 79:3938–3948

    PubMed  CAS  Article  Google Scholar 

  32. Huh WK, Roden RBS (2008) The future of vaccines for cervical cancer. Gynecol Oncol 109:S48–S56

    PubMed  CAS  Article  Google Scholar 

  33. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (2007) IARC Working Group on the evaluation of carcinogenic risks to humans, vol 90. International Agency for Research on Cancer, Lyons

    Google Scholar 

  34. Ishii Y, Ozaki S, Tanaka K, Kanda T (2005) Human papillomavirus 16 minor capsid protein L2 helps capsomeres assemble independently of intercapsomeric disulfide bonding. Virus Genes 31:321–328

    PubMed  CAS  Article  Google Scholar 

  35. Kämper N, Day PM, Nowak T, Selinka H-C, Florin L, Bolscher J, Hilbig L, Schiller JT, Sapp M (2006) A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes. J Virol 80:759–768

    PubMed  Article  CAS  Google Scholar 

  36. Kawana K, Matsumoto K, Yoshikawa H, Taketani Y, Kawana T, Yoshiike K, Kanda T (1998) A surface immunodeterminant of human papillomavirus type 16 minor capsid protein L2. Virology 245:353–359

    PubMed  CAS  Article  Google Scholar 

  37. Kawana K, Kawana Y, Yoshikawa H, Taketani Y, Yoshiike K, Kanda T (2001) Nasal immunization of mice with peptide having a cross-neutralization epitope on minor capsid protein L2 of human papillomavirus type 16 elicit systemic and mucosal antibodies. Vaccine 19:1496–1502

    PubMed  CAS  Article  Google Scholar 

  38. Kawana K, Yoshikawa H, Taketani Y, Yoshiike K, Kanda T (1999) Common neutralization epitope in minor capsid protein L2 of human papillomavirus types 16 and 6. J Virol 73:6188–6190

    PubMed  CAS  Google Scholar 

  39. Kieback E, Müller M (2006) Factors influencing subcellular localization of the human papillomavirus L2 minor structural protein. Virology 345:199–208

    PubMed  CAS  Article  Google Scholar 

  40. Knappe M, Bodevin S, Selinka H-C, Spillman D, Streek RE, Chen XS, Lindahl U, Sapp M (2007) Surface-exposed amino acid residues of HPV16 L1 protein mediating interaction with cell surface heparan sulfate. J Biol Chem 282:27913–27922

    PubMed  CAS  Article  Google Scholar 

  41. Kondo K, Ishii Y, Ochi H, Matsumoto T, Yoshikawa H, Kanda T (2007) Neutralization of HPV 16, 18, 31, and 58 pseudovirions with antisera induced by immunizing rabbits with synthetic peptides representing segments of the HPV 16 minor capsid protein L2 surface region. Virology 358:266–272

    PubMed  CAS  Article  Google Scholar 

  42. Laniosz V, Holthusen KA, Meneses PI (2008) Bovine papillomavirus type 1: from clathrin to caveolin. J Virol 82:6288–6298

    PubMed  CAS  Article  Google Scholar 

  43. Laniosz V, Nguyen KC, Meneses PI (2007) Bovine papillomavirus type 1 infection is mediated by SNARE syntaxin 18. J Virol 81:7435–7448

    PubMed  CAS  Article  Google Scholar 

  44. Lin Z, Gambhira R, Jagu S, Kirnbauer R, Meyers C, Roden RBS (2007) Subcellular localization of human papillomavirus minor capsid protein L2 differs upon ectopic versus endogenous expression. 1A-03 international papillomavirus society and Chinese medical association, 24th international papillomavirus conference, Beijing

  45. Liu WJ, Gissmann L, Sun XY, Kanjanahaluethai A, Muller M, Doorbar J, Zhou J (1997) Sequence close to the N-terminus of L2 protein is displayed on the surface of bovine papillomavirus type 1 virions. Virology 227:474–483

    PubMed  CAS  Article  Google Scholar 

  46. Mahdavi A, Monk BJ (2005) Vaccines against human papillomavirus and cervical cancer: promises and challenges. Oncologist 10:528–538

    PubMed  CAS  Article  Google Scholar 

  47. Modis Y, Trus BL, Harrison SC (2002) Atomic model of the papillomavirus capsid. Eur Mol Biol Organ J 21:4754–4762

    CAS  Google Scholar 

  48. Olcese VA, Chen Y, Schlegel R, Yuan H (2004) Characterization of HPV 16 L1 loop domains in the formation of a type-specific, conformational epitope. BMC Microbiol 4:29

    PubMed  Article  CAS  Google Scholar 

  49. Orth G, Favre M (1985) Human papillomaviruses. Biochemical and biological properties. Clin Dermatol 3:27–42

    PubMed  CAS  Article  Google Scholar 

  50. Orth G, Favre M, Croissant O (1977) Characterization of a new type of human papillomavirus that causes skin warts. J Virol 24:108–120

    PubMed  CAS  Google Scholar 

  51. Pastrana DV, Gambhira R, Buck CB, Pang Y-YS, Thompson CD, Culp TD, Christensen ND, Lowy D, Schiller JT, Roden RBS (2005) Cross-neutralization of cutaneous and mucosal papillomavirus types with anti-sera to the amino terminus of L2. Virology 337:365–372

    PubMed  CAS  Article  Google Scholar 

  52. Quint WGV, Pagliusi SR, Lelie N, de Villiers E-M, Wheeler CM, World Health Organization Human Papillomavirus DNA International Collaborative Study Group (2006) Results of the First World Health Organization international collaborative study of detection of human paillomavirus DNA. J Clin Microbiol 44:571–579

    PubMed  CAS  Article  Google Scholar 

  53. Richards RM, Lowy D, Schiller JT, Day PM (2006) Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc Natl Acad Sci USA 103:1522–1527

    PubMed  CAS  Article  Google Scholar 

  54. Rippe RA, Meinke WJ (1989) Identification and characterization of the BPV-2 L2 protein. Virology 171:298–301

    PubMed  CAS  Article  Google Scholar 

  55. Roden RBS, Yuty W, Fallon R, Inglis S, Lowy D, Schiller JT (2000) Minor capsid protein of human genital papillomavirus contains subdominant, cross-neutralizing epitopes. Virology 270:254–257

    PubMed  CAS  Article  Google Scholar 

  56. Sapp M, Fligge C, Petzak J, Harris J, Streek RE (1998) Papillomavirus assembly requires trimerization of the major capsid protein by disulfides between two highly conserved cysteines. J Virol 72:6186–6189

    PubMed  CAS  Google Scholar 

  57. Schelhaas M, Ewers H, Rajamaki ML, Day PM, Schiller JT, Helenius A (2008) Human papillomavirus type 16 entry: retrograde cell surface transport along actin-rich protrusions. PLoS Pathog 4:e1000148

    PubMed  Article  CAS  Google Scholar 

  58. Selinka H-C, Florin L, Patel HD, Freitag K, Schmidtke M, Makarov VA, Sapp M (2007) Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol 81:10970–10980

    PubMed  CAS  Article  Google Scholar 

  59. Sette A, Fikes J (2003) Epitope-based vaccines: an update on epitope identification, vaccine design and delivery. Curr Opin Immunol 15:470

    Article  CAS  Google Scholar 

  60. Slupetzky K, Gambhira R, Culp TD, Shafti-Keramat S, Schellenbacher C, Christensen ND, Roden RBS, Kirnbauer R (2007) A papillomavirus-like particle (VLP) vaccine displaying HPV 16 L2 epitopes induces cross-neutralizing antibodies to HPV 11. Vaccine 25:2001–2010

    PubMed  CAS  Article  Google Scholar 

  61. Smith JL, Campos SK, Ozbun MA (2007) Human papillomavirus type 31 uses a caveolin 1- and dynamin 2-mediated entry pathway for infection of human keratinocytes. J Virol 81:9922–9931

    PubMed  CAS  Article  Google Scholar 

  62. Trottier H, Franco EL (2006) The epidemiology of genital human papillomavirus infection. Vaccine 24(Suppl 1):S1–S15

    PubMed  Google Scholar 

  63. Trus BL, Buck CB, Cheng N, Lowy D, Steven AC, Schiller JT (2005) Localization of the HPV-16 minor capsid L2 by difference imaging. Microsc Microanal 11:642–643

    Article  Google Scholar 

  64. van der Most RB, Murali-Krishna K, Lanier JG, Wherry EJ, Puglielli MT, Blattman JN, Sette A, Ahmed R (2003) Changing immunodominance patterns in antiviral CD8 T-cell responses after loss of epitope presentation or chronic antigenic stimulation. Virology 315:93–102

    PubMed  Article  CAS  Google Scholar 

  65. Varsani A, Williamson AL, de Villiers D, Becker I, Christensen ND, Rybicki EP (2003) Chimeric human papillomavirus type 16 (HPV-16) L1 particles presenting the common neutralizing epitope for the L2 minor capsid protein of HPV-6 and HPV-16. J Virol 77:8386–8393

    PubMed  CAS  Article  Google Scholar 

  66. Villa LL, Ault KA, Giuliano AR, Costa RLR, Brown DR, Ferenczy A, Harper DM, Koutsky LA, Kurman RJ, Lehtinen M, Malm C, Olsson S-E, Ronnett BM, Skjeldestad FE, Steinwall M, Stoler MH, Wheeler CM, Taddeo FJ, Yu J, Lupinacci L, Railkar R, Marchese R, Esser MT, Bryan J, Jansen KU, Sings HL, Tamus GM, Saah AJ, Barr E (2006) Immunologic responses following administration of a vaccine targeting human papillomavirus types 6, 11, 16, and 18. Vaccine 24:5571–5583

    PubMed  CAS  Article  Google Scholar 

  67. Volpers C, Sapp M, Snijders PJF, Walboomers JMM, Streek RE (1995) Conformational and linear epitopes on virus-like particles of human papillomavirus type 33 identified by monoclonal antibodies to the minor capsid protein L2. J Gen Virol 76:2661–2667

    PubMed  CAS  Article  Google Scholar 

  68. Yang R, Day PM, Yutzy IV WH, Lin K, Hung C-F, Roden BS (2003) Cell surface-binding motifs of L2 that facilitate papillomavirus infection. J Virol 77:3531–3541

    PubMed  CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Edward P. Rybicki.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pereira, R., Hitzeroth, I.I. & Rybicki, E.P. Insights into the role and function of L2, the minor capsid protein of papillomaviruses. Arch Virol 154, 187–197 (2009). https://doi.org/10.1007/s00705-009-0310-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-009-0310-3

Keywords

  • Genital Wart
  • Major Capsid Protein
  • Cervical Cancer Case
  • Cervarix
  • Furin Cleavage