1887

Abstract

Human papillomaviruses (HPVs) are the most common sexually transmitted viruses and one of the most important infectious causes of cancers worldwide. While prophylactic vaccines are effective against certain strains of HPV, established infections still cause deadly cancers in both men and women. HPV traffics to the nucleus via the retrograde transport pathway, but the mechanism of intracellular transport of non-enveloped viruses such as HPV is incompletely understood. Using an overexpression screen, we identify several genes that control HPV16 entry. We focused on the mechanism by which one of the screen hits, stannin, blocks HPV16 infection. Stannin has not been previously implicated in virus entry. Overexpression of stannin specifically inhibits infection by several HPV types, but not other viruses tested. Stannin is constitutively expressed in human keratinocytes, and its basal levels limit entry by HPV16. Stannin is localized to the endolysosomal compartment and does not affect HPV16 binding to cells, virus uptake, or virus uncoating, but inhibits the entry of HPV into the trans-Golgi network (TGN) and stimulates HPV degradation. We further show that stannin interacts with L1 major capsid protein and impairs the interaction of the L2 minor capsid protein with retromer, which is required for virus trafficking to the TGN. Our findings shed light on a novel cellular protein that interferes with HPV entry and highlight the role of retrograde transport in HPV entry.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000954
2017-11-01
2020-01-23
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/11/2821.html?itemId=/content/journal/jgv/10.1099/jgv.0.000954&mimeType=html&fmt=ahah

References

  1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–3044 [CrossRef][PubMed]
    [Google Scholar]
  2. Psyrri A, DiMaio D. Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol 2008;5:24–31 [CrossRef][PubMed]
    [Google Scholar]
  3. Richards KF, Bienkowska-Haba M, Dasgupta J, Chen XS, Sapp M. Multiple heparan sulfate binding site engagements are required for the infectious entry of human papillomavirus type 16. J Virol 2013;87:11426–11437 [CrossRef][PubMed]
    [Google Scholar]
  4. Cerqueira C, Samperio Ventayol P, Vogeley C, Schelhaas M. Kallikrein-8 proteolytically processes human papillomaviruses in the extracellular space to facilitate entry into host cells. J Virol 2015;89:7038–7052 [CrossRef][PubMed]
    [Google Scholar]
  5. Richards RM, Lowy DR, Schiller JT, Day PM. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc Natl Acad Sci USA 2006;103:1522–1527 [CrossRef][PubMed]
    [Google Scholar]
  6. Raff AB, Woodham AW, Raff LM, Skeate JG, Yan L et al. The evolving field of human papillomavirus receptor research: a review of binding and entry. J Virol 2013;87:6062–6072 [CrossRef][PubMed]
    [Google Scholar]
  7. Schelhaas M, Shah B, Holzer M, Blattmann P, Kühling L et al. Entry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis. PLoS Pathog 2012;8:e1002657 [CrossRef][PubMed]
    [Google Scholar]
  8. Lipovsky A, Popa A, Pimienta G, Wyler M, Bhan A et al. Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus. Proc Natl Acad Sci USA 2013;110:7452–7457 [CrossRef][PubMed]
    [Google Scholar]
  9. Day PM, Thompson CD, Schowalter RM, Lowy DR, Schiller JT. Identification of a role for the trans-Golgi network in human papillomavirus 16 pseudovirus infection. J Virol 2013;87:3862–3870 [CrossRef][PubMed]
    [Google Scholar]
  10. Zhang W, Kazakov T, Popa A, DiMaio D. Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires γ-secretase activity. MBio 2014;5:e01777-1401714 [CrossRef][PubMed]
    [Google Scholar]
  11. Laniosz V, Dabydeen SA, Havens MA, Meneses PI. Human papillomavirus type 16 infection of human keratinocytes requires clathrin and caveolin-1 and is brefeldin a sensitive. J Virol 2009;83:8221–8232 [CrossRef][PubMed]
    [Google Scholar]
  12. Gräßel L, Fast LA, Scheffer KD, Boukhallouk F, Spoden GA et al. The CD63-syntenin-1 complex controls post-endocytic trafficking of oncogenic human papillomaviruses. Sci Rep 2016;6:32337 [CrossRef][PubMed]
    [Google Scholar]
  13. Pyeon D, Pearce SM, Lank SM, Ahlquist P, Lambert PF. Establishment of human papillomavirus infection requires cell cycle progression. PLoS Pathog 2009;5:e1000318 [CrossRef][PubMed]
    [Google Scholar]
  14. Aydin I, Weber S, Snijder B, Samperio Ventayol P, Kühbacher A et al. Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses. PLoS Pathog 2014;10:e1004162 [CrossRef][PubMed]
    [Google Scholar]
  15. Aydin I, Villalonga-Planells R, Greune L, Bronnimann MP, Calton CM et al. A central region in the minor capsid protein of papillomaviruses facilitates viral genome tethering and membrane penetration for mitotic nuclear entry. PLoS Pathog 2017;13:e1006308 [CrossRef][PubMed]
    [Google Scholar]
  16. Calton CM, Bronnimann MP, Manson AR, Li S, Chapman JA et al. Translocation of the papillomavirus L2/vDNA complex across the limiting membrane requires the onset of mitosis. PLoS Pathog 2017;13:e1006200 [CrossRef][PubMed]
    [Google Scholar]
  17. DiGiuseppe S, Luszczek W, Keiffer TR, Bienkowska-Haba M, Guion LG et al. Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis. Proc Natl Acad Sci USA 2016;113:6289–6294 [CrossRef][PubMed]
    [Google Scholar]
  18. Broniarczyk J, Massimi P, Bergant M, Banks L. Human papillomavirus infectious entry and trafficking is a rapid process. J Virol 2015;89:8727–8732 [CrossRef][PubMed]
    [Google Scholar]
  19. Kajitani N, Satsuka A, Kawate A, Sakai H. Productive lifecycle of human papillomaviruses that depends upon squamous epithelial differentiation. Front Microbiol 2012;3:152 [CrossRef][PubMed]
    [Google Scholar]
  20. DiGiuseppe S, Bienkowska-Haba M, Guion LG, Sapp M. Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus. Virus Res 2017;231:1–9 [CrossRef][PubMed]
    [Google Scholar]
  21. Buck CB, Pastrana DV, Lowy DR, Schiller JT. Generation of HPV pseudovirions using transfection and their use in neutralization assays. Methods Mol Med 2005;119:445–462 [CrossRef][PubMed]
    [Google Scholar]
  22. Popa A, Zhang W, Harrison MS, Goodner K, Kazakov T et al. Direct binding of retromer to human papillomavirus type 16 minor capsid protein L2 mediates endosome exit during viral infection. PLoS Pathog 2015;11:e1004699 [CrossRef][PubMed]
    [Google Scholar]
  23. Bergant Marušič M, Ozbun MA, Campos SK, Myers MP, Banks L. Human papillomavirus L2 facilitates viral escape from late endosomes via sorting nexin 17. Traffic 2012;13:455–467 [CrossRef][PubMed]
    [Google Scholar]
  24. Wang JW, Roden RB. L2, the minor capsid protein of papillomavirus. Virology 2013;445:175–186 [CrossRef][PubMed]
    [Google Scholar]
  25. Pim D, Broniarczyk J, Bergant M, Playford MP, Banks L. A Novel PDZ domain interaction mediates the binding between human papillomavirus 16 L2 and sorting nexin 27 and modulates virion trafficking. J Virol 2015;89:10145–10155 [CrossRef][PubMed]
    [Google Scholar]
  26. Burd C, Cullen PJ. Retromer: a master conductor of endosome sorting. Cold Spring Harb Perspect Biol 2014;6:pii: a016774 [CrossRef][PubMed]
    [Google Scholar]
  27. Bronnimann MP, Chapman JA, Park CK, Campos SK. A transmembrane domain and GxxxG motifs within L2 are essential for papillomavirus infection. J Virol 2013;87:464–473 [CrossRef][PubMed]
    [Google Scholar]
  28. DiGiuseppe S, Keiffer TR, Bienkowska-Haba M, Luszczek W, Guion LG et al. Topography of the human papillomavirus minor capsid protein L2 during vesicular trafficking of infectious entry. J Virol 2015;89:10442–10452 [CrossRef][PubMed]
    [Google Scholar]
  29. Kämper N, Day PM, Nowak T, Selinka HC, Florin L et al. A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes. J Virol 2006;80:759–768 [CrossRef][PubMed]
    [Google Scholar]
  30. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 2011;1:519–525 [CrossRef][PubMed]
    [Google Scholar]
  31. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014;32:513–545 [CrossRef][PubMed]
    [Google Scholar]
  32. Warren CJ, Xu T, Guo K, Griffin LM, Westrich JA et al. APOBEC3A functions as a restriction factor of human papillomavirus. J Virol 2015;89:688–702 [CrossRef][PubMed]
    [Google Scholar]
  33. Day PM, Thompson CD, Lowy DR, Schiller JT. Interferon gamma prevents infectious entry of human papillomavirus 16 via an L2-dependent mechanism. J Virol 2017;91:e00168-1700168117 [CrossRef][PubMed]
    [Google Scholar]
  34. Habiger C, Jäger G, Walter M, Iftner T, Stubenrauch F. Interferon kappa inhibits human papillomavirus 31 transcription by inducing Sp100 proteins. J Virol 2015;90:694–704 [CrossRef][PubMed]
    [Google Scholar]
  35. Dittmann M, Hoffmann HH, Scull MA, Gilmore RH, Bell KL et al. A serpin shapes the extracellular environment to prevent influenza A virus maturation. Cell 2015;160:631–643 [CrossRef][PubMed]
    [Google Scholar]
  36. Barr BB, Benton EC, Mclaren K, Bunney MH, Smith IW et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet 1989;2:224–225 [CrossRef][PubMed]
    [Google Scholar]
  37. Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA et al. Functional and structural properties of stannin: roles in cellular growth, selective toxicity, and mitochondrial responses to injury. J Cell Biochem 2006;98:243–250 [CrossRef][PubMed]
    [Google Scholar]
  38. Toggas SM, Krady JK, Billingsley ML. Molecular neurotoxicology of trimethyltin: identification of stannin, a novel protein expressed in trimethyltin-sensitive cells. Mol Pharmacol 1992;42:44–56[PubMed]
    [Google Scholar]
  39. Fagerberg L, Hallstrom BJ, Lindskog C, Uhlen M et al. Tissue-based map of the human proteome. Science 2015;347:12604191–12604199
    [Google Scholar]
  40. Griffin LM, Cicchini L, Pyeon D. Human papillomavirus infection is inhibited by host autophagy in primary human keratinocytes. Virology 2013;437:12–19 [CrossRef][PubMed]
    [Google Scholar]
  41. Surviladze Z, Sterk RT, Deharo SA, Ozbun MA. Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy. J Virol 2013;87:2508–2517 [CrossRef][PubMed]
    [Google Scholar]
  42. Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 2005;280:20722–20729 [CrossRef][PubMed]
    [Google Scholar]
  43. Reese BE, Krissinger D, Yun JK, Billingsley ML. Elucidation of stannin function using microarray analysis: implications for cell cycle control. Gene Expr 2006;13:41–52 [CrossRef][PubMed]
    [Google Scholar]
  44. Bronnimann MP, Calton CM, Chiquette SF, Li S, Lu M et al. Furin cleavage of L2 during papillomavirus infection: minimal dependence on cyclophilins. J Virol 2016;90:6224–6234 [CrossRef][PubMed]
    [Google Scholar]
  45. Ishii Y, Tanaka K, Kondo K, Takeuchi T, Mori S et al. Inhibition of nuclear entry of HPV16 pseudovirus-packaged DNA by an anti-HPV16 L2 neutralizing antibody. Virology 2010;406:181–188 [CrossRef][PubMed]
    [Google Scholar]
  46. Leifer CA, Kennedy MN, Mazzoni A, Lee C, Kruhlak MJ et al. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J Immunol 2004;173:1179–1183 [CrossRef][PubMed]
    [Google Scholar]
  47. Sapp M, Kraus U, Volpers C, Snijders PJ, Walboomers JM et al. Analysis of type-restricted and cross-reactive epitopes on virus-like particles of human papillomavirus type 33 and in infected tissues using monoclonal antibodies to the major capsid protein. J Gen Virol 1994;75:3375–3383 [CrossRef][PubMed]
    [Google Scholar]
  48. Söderberg O, Gullberg M, Jarvius M, Ridderstråle K, Leuchowius KJ et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 2006;3:995–1000 [CrossRef][PubMed]
    [Google Scholar]
  49. Lipovsky A, Zhang W, Iwasaki A, DiMaio D. Application of the proximity-dependent assay and fluorescence imaging approaches to study viral entry pathways. Methods Mol Biol 2015;1270:437–451 [CrossRef][PubMed]
    [Google Scholar]
  50. Daulat AM, Maurice P, Froment C, Guillaume JL, Broussard C et al. Purification and identification of G protein-coupled receptor protein complexes under native conditions. Mol Cell Proteomics 2007;6:835–844 [CrossRef][PubMed]
    [Google Scholar]
  51. Chinnapen DJ, Chinnapen H, Saslowsky D, Lencer WI. Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER. FEMS Microbiol Lett 2007;266:129–137 [CrossRef][PubMed]
    [Google Scholar]
  52. Seaman MN. Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 2004;165:111–122 [CrossRef][PubMed]
    [Google Scholar]
  53. Schoggins JW, Macduff DA, Imanaka N, Gainey MD, Shrestha B et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 2014;505:691–695 [CrossRef][PubMed]
    [Google Scholar]
  54. Molejon MI, Ropolo A, Re AL, Boggio V, Vaccaro MI. The VMP1-Beclin 1 interaction regulates autophagy induction. Sci Rep 2013;3:1055 [CrossRef][PubMed]
    [Google Scholar]
  55. Sapp MJ. HPV virions hitchhike a ride on retromer complexes. Proc Natl Acad Sci USA 2013;110:7116–7117 [CrossRef][PubMed]
    [Google Scholar]
  56. Zhang J, Reiling C, Reinecke JB, Prislan I, Marky LA et al. Rabankyrin-5 interacts with EHD1 and Vps26 to regulate endocytic trafficking and retromer function. Traffic 2012;13:745–757 [CrossRef][PubMed]
    [Google Scholar]
  57. DiGiuseppe S, Bienkowska-Haba M, Guion LGM, Keiffer TR, Sapp M. Human papillomavirus major capsid protein L1 remains associated with the incoming viral genome throughout the entry process. J Virol 2017;e00537-17 [CrossRef][PubMed]
    [Google Scholar]
  58. Wiens ME, Smith JG. α-defensin HD5 inhibits human papillomavirus 16 infection via capsid stabilization and redirection to the lysosome. MBio 2017;8:e02304-16 [CrossRef][PubMed]
    [Google Scholar]
  59. Griffin LM, Cicchini L, Xu T, Pyeon D. Human keratinocyte cultures in the investigation of early steps of human papillomavirus infection. Methods Mol Biol 2014;1195:219–238 [CrossRef][PubMed]
    [Google Scholar]
  60. Goodwin EC, Yang E, Lee CJ, Lee HW, DiMaio D et al. Rapid induction of senescence in human cervical carcinoma cells. Proc Natl Acad Sci USA 2000;97:10978–10983 [CrossRef][PubMed]
    [Google Scholar]
  61. Desai P, Person S. Incorporation of the green fluorescent protein into the herpes simplex virus type 1 capsid. J Virol 1998;72:7563–7568[PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000954
Loading
/content/journal/jgv/10.1099/jgv.0.000954
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited articles

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