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Volume 101, Issue 9

Acquisition of a phospho-acceptor site enhances HPV E6 PDZ-binding motif functional promiscuity Free

Abstract

All cancer-causing human papillomavirus (HPV) E6 oncoproteins have a C-terminal PDZ-binding motif (PBM), which correlates with oncogenic potential. Nonetheless, several HPVs with little or no oncogenic potential also have an E6 PBM, with minor sequence differences affecting PDZ protein selectivity. Furthermore, certain HPV types have a phospho-acceptor site embedded within the PBM. We therefore compared HPV-18, HPV-66 and HPV-40 E6 proteins to examine the possible link between the ability to target multiple PDZ proteins and the acquisition of a phospho-acceptor site. The mutation of essential residues in HPV-18E6 reduces its phosphorylation, and fewer PDZ substrates are bound. In contrast, the generation of consensus phospho-acceptor sites in HPV-66 and HPV-40 E6 PBMs increases the PDZ proteins recognized. Thus, although phosphorylation of the E6 PBM and PDZ protein recognition are mutually exclusive, they are closely linked, with the acquisition of a phospho-acceptor site also contributing to an expansion in the number of PDZ proteins bound.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): HPV E6 , PBM , PDZ and phosphorylation
© 2020 The Authors
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/content/journal/jgv/10.1099/jgv.0.001236
2019-02-27
2024-04-18
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References

  1. Zur Hausen H, Gissmann L, Steiner W, Dippold W, Dreger I. Human papilloma viruses and cancer. Bibl Haematol 1975; 43:569–571
     [Google Scholar]
  2. Human Iwgoteocrt Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr Eval Carcinog Risks Hum 2012; 100:1–441
     [Google Scholar]
  3. Ciapponi A, Bardach A, Glujovsky D, Gibbons L, Picconi MA. Type-specific HPV prevalence in cervical cancer and high-grade lesions in Latin America and the Caribbean: systematic review and meta-analysis. PLoS One 2011; 6:e25493 [View Article][PubMed]
     [Google Scholar]
  4. Bruni L, Diaz M, Castellsagué X, Ferrer E, Bosch FX et al. Cervical human papillomavirus prevalence in 5 continents: meta-analysis of 1 million women with normal cytological findings. J Infect Dis 2010; 202:1789–1799 [View Article][PubMed]
     [Google Scholar]
  5. Bouvard V, Baan R, Straif K, Grosse Y, Secretan B et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol 2009; 10:321–322 [View Article][PubMed]
     [Google Scholar]
  6. Kovacic MB, Castle PE, Herrero R, Schiffman M, Sherman ME et al. Relationships of human papillomavirus type, qualitative viral load, and age with cytologic abnormality. Cancer Res 2006; 66:10112–10119 [View Article][PubMed]
     [Google Scholar]
  7. Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S et al. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005; 337:76–84 [View Article][PubMed]
     [Google Scholar]
  8. Schiffman M, Doorbar J, Wentzensen N, de Sanjosé S, Fakhry C et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2016; 2:16086 [View Article][PubMed]
     [Google Scholar]
  9. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M et al. The biology and life-cycle of human papillomaviruses. Vaccine 2012; 30:F55–70 [View Article][PubMed]
     [Google Scholar]
  10. Meisal R, Rounge TB, Christiansen IK, Eieland AK, Worren MM et al. HPV genotyping of modified general primer-amplicons is more analytically sensitive and specific by sequencing than by hybridization. PLoS One 2017; 12:e0169074 [View Article][PubMed]
     [Google Scholar]
  11. de Villiers EM, Fauquet C, Broker TR, Bernard HU, Zur Hausen H. Classification of papillomaviruses. Virology 2004; 324:17–27 [View Article][PubMed]
     [Google Scholar]
  12. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009; 4:8 [View Article][PubMed]
     [Google Scholar]
  13. Münger K, Werness BA, Dyson N, Phelps WC, Harlow E et al. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. Embo J 1989; 8:4099–4105[PubMed]
     [Google Scholar]
  14. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res 1996; 56:4620–4624[PubMed]
     [Google Scholar]
  15. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990; 63:1129–1136[PubMed]
     [Google Scholar]
  16. Thomas M, Banks L. Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene 1998; 17:2943–2954 [View Article][PubMed]
     [Google Scholar]
  17. Thomas M, Banks L. Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 1999; 80:1513–1517 [View Article][PubMed]
     [Google Scholar]
  18. Javier RT. Cell polarity proteins: common targets for tumorigenic human viruses. Oncogene 2008; 27:7031–7046 [View Article][PubMed]
     [Google Scholar]
  19. Culp TD, Cladel NM, Balogh KK, Budgeon LR, Mejia AF et al. Papillomavirus particles assembled in 293TT cells are infectious in vivo . J Virol 2006; 80:11381–11384 [View Article][PubMed]
     [Google Scholar]
  20. Pim D, Bergant M, Boon SS, Ganti K, Kranjec C et al. Human papillomaviruses and the specificity of PDZ domain targeting. Febs J 2012; 279:3530–3537 [View Article][PubMed]
     [Google Scholar]
  21. Nicolaides L, Davy C, Raj K, Kranjec C, Banks L et al. Stabilization of HPV16 E6 protein by PDZ proteins, and potential implications for genome maintenance. Virology 2011; 414:137–145 [View Article][PubMed]
     [Google Scholar]
  22. Watson RA, Thomas M, Banks L, Roberts S. Activity of the human papillomavirus E6 PDZ-binding motif correlates with an enhanced morphological transformation of immortalized human keratinocytes. J Cell Sci 2003; 116:4925–4934 [View Article][PubMed]
     [Google Scholar]
  23. Thomas M, Massimi P, Navarro C, Borg JP, Banks L. The hScrib/Dlg apico-basal control complex is differentially targeted by HPV-16 and HPV-18 E6 proteins. Oncogene 2005; 24:6222–6230 [View Article][PubMed]
     [Google Scholar]
  24. Thomas M, Myers MP, Massimi P, Guarnaccia C, Banks L. Analysis of multiple HPV E6 PDZ interactions defines type-specific PDZ fingerprints that predict oncogenic potential. PLoS Pathog 2016; 12:e1005766 [View Article][PubMed]
     [Google Scholar]
  25. Massimi P, Gammoh N, Thomas M, Banks L. HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation. Oncogene 2004; 23:8033–8039 [View Article][PubMed]
     [Google Scholar]
  26. Massimi P, Shai A, Lambert P, Banks L. HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background. Oncogene 2008; 27:1800–1804 [View Article][PubMed]
     [Google Scholar]
  27. Kuballa P, Matentzoglu K, Scheffner M. The role of the ubiquitin ligase E6-AP in human papillomavirus E6-mediated degradation of PDZ domain-containing proteins. J Biol Chem 2007; 282:65–71 [View Article][PubMed]
     [Google Scholar]
  28. Zhang Y, Dasgupta J, Ma RZ, Banks L, Thomas M et al. Structures of a human papillomavirus (HPV) E6 polypeptide bound to MAGUK proteins: mechanisms of targeting tumor suppressors by a high-risk HPV oncoprotein. J Virol 2007; 81:3618–3626 [View Article][PubMed]
     [Google Scholar]
  29. Thomas M, Narayan N, Pim D, Tomaić V, Massimi P et al. Human papillomaviruses, cervical cancer and cell polarity. Oncogene 2008; 27:7018–7030 [View Article][PubMed]
     [Google Scholar]
  30. Charbonnier S, Stier G, Orfanoudakis G, Kieffer B, Atkinson RA et al. Defining the minimal interacting regions of the tight junction protein MAGI-1 and HPV16 E6 oncoprotein for solution structure studies. Protein Expr Purif 2008; 60:64–73 [View Article][PubMed]
     [Google Scholar]
  31. Fournane S, Charbonnier S, Chapelle A, Kieffer B, Orfanoudakis G et al. Surface plasmon resonance analysis of the binding of high-risk mucosal HPV E6 oncoproteins to the PDZ1 domain of the tight junction protein MAGI-1. J Mol Recognit 2011; 24:511–523 [View Article][PubMed]
     [Google Scholar]
  32. Tonikian R, Zhang Y, Sazinsky SL, Currell B, Yeh JH et al. A specificity map for the PDZ domain family. PLoS Biol 2008; 6:e239 [View Article][PubMed]
     [Google Scholar]
  33. Tomaić V, Gardiol D, Massimi P, Ozbun M, Myers M et al. Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene 2009; 28:1–8 [View Article][PubMed]
     [Google Scholar]
  34. van Doorslaer K, Desalle R, Einstein MH, Burk RD. Degradation of human PDZ-Proteins by human alphapapillomaviruses represents an evolutionary adaptation to a novel cellular niche. PLoS Pathog 2015; 11:e1004980 [View Article][PubMed]
     [Google Scholar]
  35. Boon SS, Banks L. High-risk human papillomavirus E6 oncoproteins interact with 14-3-3ζ in a PDZ binding motif-dependent manner. J Virol 2013; 87:1586–1595 [View Article][PubMed]
     [Google Scholar]
  36. Boon SS, Tomaić V, Thomas M, Roberts S, Banks L. Cancer-causing human papillomavirus E6 proteins display major differences in the phospho-regulation of their PDZ interactions. J Virol 2015; 89:1579–1586 [View Article][PubMed]
     [Google Scholar]
  37. Delury CP, Marsh EK, James CD, Boon SS, Banks L et al. The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18. J Virol 2013; 87:9463–9472 [View Article][PubMed]
     [Google Scholar]
  38. Thatte J, Massimi P, Thomas M, Boon SS, Banks L. The human papillomavirus E6 PDZ binding motif links DNA damage response signaling to E6 inhibition of p53 transcriptional activity. J Virol 2018; 92: [View Article][PubMed]
     [Google Scholar]
  39. Gardiol D, Galizzi S, Banks L. Mutational analysis of the discs large tumour suppressor identifies domains responsible for human papillomavirus type 18 E6-mediated degradation. J Gen Virol 2002; 83:283–289 [View Article][PubMed]
     [Google Scholar]
  40. Kranjec C, Massimi P, Banks L. Restoration of MAGI-1 expression in human papillomavirus-positive tumor cells induces cell growth arrest and apoptosis. J Virol 2014; 88:7155–7169 [View Article][PubMed]
     [Google Scholar]
  41. Kranjec C, Tomaić V, Massimi P, Nicolaides L, Doorbar J et al. The high-risk HPV E6 target scribble (hScrib) is required for HPV E6 expression in cervical tumour-derived cell lines. Papillomavirus Res 2016; 2:70–77 [View Article][PubMed]
     [Google Scholar]
  42. Wigler M, Sweet R, Sim GK, Wold B, Pellicer A et al. Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell 1979; 16:777–785[PubMed]
     [Google Scholar]
  43. Muench P, Hiller T, Probst S, Florea AM, Stubenrauch F et al. Binding of PDZ proteins to HPV E6 proteins does neither correlate with epidemiological risk classification nor with the immortalization of foreskin keratinocytes. Virology 2009; 387:380–387 [View Article][PubMed]
     [Google Scholar]
  44. James CD, Roberts S. Viral interactions with PDZ domain-containing proteins-an oncogenic trait?. Pathogens 2016; 5: [View Article][PubMed]
     [Google Scholar]
  45. Chen Z, Terai M, Fu L, Herrero R, Desalle R et al. Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses. J Virol 2005; 79:7014–7023 [View Article][PubMed]
     [Google Scholar]
  46. Hildesheim A, Schiffman M, Bromley C, Wacholder S, Herrero R et al. Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 2001; 93:315–318[PubMed]
     [Google Scholar]
  47. Kim J, Kim I, Yang JS, Shin YE, Hwang J et al. Rewiring of PDZ domain-ligand interaction network contributed to eukaryotic evolution. PLoS Genet 2012; 8:e1002510 [View Article][PubMed]
     [Google Scholar]
  48. Hung AY, Sheng M. PDZ domains: structural modules for protein complex assembly. J Biol Chem 2002; 277:5699–5702 [View Article][PubMed]
     [Google Scholar]
  49. Nguyen ML, Nguyen MM, Lee D, Griep AE, Lambert PF. The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6's induction of epithelial hyperplasia in vivo . J Virol 2003; 77:6957–6964[PubMed]
     [Google Scholar]
  50. Nourry C, Grant SG, Borg JP. PDZ domain proteins: plug and play!. Sci STKE 2003; 2003:RE7 [View Article][PubMed]
     [Google Scholar]
  51. Lee HJ, Zheng JJ. PDZ domains and their binding partners: structure, specificity, and modification. Cell Commun Signal 2010; 8:8:8 [View Article][PubMed]
     [Google Scholar]
  52. Kühne C, Gardiol D, Guarnaccia C, Amenitsch H, Banks L. Differential regulation of human papillomavirus E6 by protein kinase A: conditional degradation of human discs large protein by oncogenic E6. Oncogene 2000; 19:5884–5891[PubMed]
     [Google Scholar]
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Acquisition of a phospho-acceptor site enhances HPV E6 PDZ-binding motif functional promiscuity
J. Gen. Virol. 101, 954 (2020); https://doi.org/10.1099/jgv.0.001236
/content/journal/jgv/10.1099/jgv.0.001236
/content/journal/jgv/10.1099/jgv.0.001236
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