1887

Abstract

Adenovirus has evolved strategies to usurp host-cell factors and machinery to facilitate its life cycle, including cell entry, replication, assembly and egress. Adenovirus continues, therefore, to be an important model system for investigating fundamental cellular processes. The role of adenovirus E1B-55k in targeting host-cell proteins that possess antiviral activity for proteasomal degradation is now well established. To expand our understanding of E1B-55k in regulating the levels of host-cell proteins, we performed comparative proteome analysis of wild-type, and E1B-55k-deletion, adenovirus-infected cancer cells. As such we performed quantitative MS/MS analysis to monitor protein expression changes affected by viral E1B-55k. We identified 5937 proteins, and of these, 69 and 58 proteins were down-regulated during wild-type and E1B-55k (1520) adenovirus infection, respectively. This analysis revealed that there are many, previously unidentified, cellular proteins subjected to degradation by adenovirus utilizing pathways independent of E1B-55k expression. Moreover, we found that ALCAM, EPHA2 and PTPRF, three cellular proteins that function in the regulation of cell–cell contacts, appeared to be degraded by E1B-55k/E4orf3 and/or E1B-55k/E4orf6 complexes. These molecules, like integrin α3 (a known substrate of E1B-55k/E4orf6), are critical regulators of cell signalling, cell adhesion and cell surface modulation, and their degradation during infection is, potentially, pertinent to adenovirus propagation. The data presented in this study illustrate the broad nature of protein down-regulation mediated by adenovirus.

Keyword(s): adenovirus , d11520 , E1B-55k and proteomics
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2017-06-01
2024-03-19
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References

  1. Rowe WP, Huebner RJ, Gilmore LK, Parrott RH, Ward TG. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proc Soc Exp Biol Med 1953; 84:570–573 [View Article][PubMed]
    [Google Scholar]
  2. Yang XJ, Ogryzko VV, Nishikawa J, Howard BH, Nakatani Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 1996; 382:319–324 [View Article][PubMed]
    [Google Scholar]
  3. Berget SM, Moore C, Sharp PA. Spliced segments at the 5' terminus of adenovirus 2 late mRNA. Proc Natl Acad Sci USA 1977; 74:3171–3175 [View Article][PubMed]
    [Google Scholar]
  4. Chow LT, Gelinas RE, Broker TR, Roberts RJ. An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA. Cell 1977; 12:1–8 [View Article][PubMed]
    [Google Scholar]
  5. Moran E. Interaction of adenoviral proteins with pRB and p53. FASEB J 1993; 7:880–885[PubMed]
    [Google Scholar]
  6. Harada JN, Shevchenko A, Shevchenko A, Pallas DC, Berk AJ. Analysis of the adenovirus E1B-55K-anchored proteome reveals its link to ubiquitination machinery. J Virol 2002; 76:9194–9206 [View Article][PubMed]
    [Google Scholar]
  7. Stracker TH, Carson CT, Weitzman MD. Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 2002; 418:348–352 [View Article][PubMed]
    [Google Scholar]
  8. Turnell AS, Grand RJ. DNA viruses and the cellular DNA-damage response. J Gen Virol 2012; 93:2076–2097 [View Article][PubMed]
    [Google Scholar]
  9. Querido E, Blanchette P, Yan Q, Kamura T, Morrison M et al. Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev 2001; 15:3104–3117 [View Article][PubMed]
    [Google Scholar]
  10. Dallaire F, Blanchette P, Groitl P, Dobner T, Branton PE. Identification of integrin alpha3 as a new substrate of the adenovirus E4orf6/E1B 55-kilodalton E3 ubiquitin ligase complex. J Virol 2009; 83:5329–5338 [View Article][PubMed]
    [Google Scholar]
  11. Baker A, Rohleder KJ, Hanakahi LA, Ketner G. Adenovirus E4 34k and E1b 55k oncoproteins target host DNA ligase IV for proteasomal degradation. J Virol 2007; 81:7034–7040 [View Article][PubMed]
    [Google Scholar]
  12. Orazio NI, Naeger CM, Karlseder J, Weitzman MD. The adenovirus E1b55K/E4orf6 complex induces degradation of the Bloom helicase during infection. J Virol 2011; 85:1887–1892 [View Article][PubMed]
    [Google Scholar]
  13. Gupta A, Jha S, Engel DA, Ornelles DA, Dutta A. Tip60 degradation by adenovirus relieves transcriptional repression of viral transcriptional activator EIA. Oncogene 2013; 32:5017–5025 [View Article][PubMed]
    [Google Scholar]
  14. Schreiner S, Bürck C, Glass M, Groitl P, Wimmer P et al. Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes. Nucleic Acids Res 2013; 41:3532–3550 [View Article][PubMed]
    [Google Scholar]
  15. Schreiner S, Kinkley S, Bürck C, Mund A, Wimmer P et al. SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection. PLoS Pathog 2013; 9:e1003775 [View Article][PubMed]
    [Google Scholar]
  16. Carvalho T, Seeler JS, Ohman K, Jordan P, Pettersson U et al. Targeting of adenovirus E1A and E4-ORF3 proteins to nuclear matrix-associated PML bodies. J Cell Biol 1995; 131:45–56 [View Article][PubMed]
    [Google Scholar]
  17. Doucas V, Ishov AM, Romo A, Juguilon H, Weitzman MD et al. Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes Dev 1996; 10:196–207 [View Article][PubMed]
    [Google Scholar]
  18. Evans JD, Hearing P. Distinct roles of the adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. J Virol 2003; 77:5295–5304 [View Article][PubMed]
    [Google Scholar]
  19. Liu Y, Shevchenko A, Shevchenko A, Berk AJ. Adenovirus exploits the cellular aggresome response to accelerate inactivation of the MRN complex. J Virol 2005; 79:14004–14016 [View Article][PubMed]
    [Google Scholar]
  20. Stracker TH, Lee DV, Carson CT, Araujo FD, Ornelles DA et al. Serotype-specific reorganization of the Mre11 complex by adenoviral E4orf3 proteins. J Virol 2005; 79:6664–6673 [View Article][PubMed]
    [Google Scholar]
  21. Forrester NA, Patel RN, Speiseder T, Groitl P, Sedgwick GG et al. Adenovirus E4orf3 targets transcriptional intermediary factor 1γ for proteasome-dependent degradation during infection. J Virol 2012; 86:3167–3179 [View Article][PubMed]
    [Google Scholar]
  22. Bridges RG, Sohn SY, Wright J, Leppard KN, Hearing P. The adenovirus E4-ORF3 protein stimulates SUMOylation of general transcription factor TFII-I to direct proteasomal degradation. MBio 2016; 7:e02184-15 [View Article][PubMed]
    [Google Scholar]
  23. Toth K, Wold WS. Increasing the efficacy of oncolytic adenovirus vectors. Viruses 2010; 2:1844–1866 [View Article][PubMed]
    [Google Scholar]
  24. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol 2012; 30:658–670 [View Article][PubMed]
    [Google Scholar]
  25. Kirn D. Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned?. Gene Ther 2001; 8:89–98 [View Article][PubMed]
    [Google Scholar]
  26. Barker DD, Berk AJ. Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology 1987; 156:107–121 [View Article][PubMed]
    [Google Scholar]
  27. Nemunaitis J, Ganly I, Khuri F, Arseneau J, Kuhn J et al. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. Cancer Res 2000; 60:6359–6366[PubMed]
    [Google Scholar]
  28. Goodrum FD, Ornelles DA. p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J Virol 1998; 72:9479–9490[PubMed]
    [Google Scholar]
  29. Harada JN, Berk AJ. p53-Independent and -dependent requirements for E1B-55K in adenovirus type 5 replication. J Virol 1999; 73:5333–5344[PubMed]
    [Google Scholar]
  30. Turnell AS, Grand RJ, Gallimore PH. The replicative capacities of large E1B-null group A and group C adenoviruses are independent of host cell p53 status. J Virol 1999; 73:2074–2083[PubMed]
    [Google Scholar]
  31. O'Shea CC, Johnson L, Bagus B, Choi S, Nicholas C et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004; 6:611–623 [View Article][PubMed]
    [Google Scholar]
  32. Woo JL, Berk AJ. Adenovirus ubiquitin-protein ligase stimulates viral late mRNA nuclear export. J Virol 2007; 81:575–587 [View Article][PubMed]
    [Google Scholar]
  33. Blanchette P, Kindsmüller K, Groitl P, Dallaire F, Speiseder T et al. Control of mRNA export by adenovirus E4orf6 and E1B55K proteins during productive infection requires E4orf6 ubiquitin ligase activity. J Virol 2008; 82:2642–2651 [View Article][PubMed]
    [Google Scholar]
  34. Aoki W, Tatsukami Y, Kitahara N, Matsui K, Morisaka H et al. Elucidation of potentially virulent factors of Candida albicans during serum adaptation by using quantitative time-course proteomics. J Proteomics 2013; 91:417–429 [View Article][PubMed]
    [Google Scholar]
  35. Matheson NJ, Sumner J, Wals K, Rapiteanu R, Weekes MP et al. Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef. Cell Host Microbe 2015; 18:409–423 [View Article][PubMed]
    [Google Scholar]
  36. Evans VC, Barker G, Heesom KJ, Fan J, Bessant C et al. De novo derivation of proteomes from transcriptomes for transcript and protein identification. Nat Methods 2012; 9:1207–1211 [View Article][PubMed]
    [Google Scholar]
  37. Chahal JS, Gallagher C, DeHart CJ, Flint SJ. The repression domain of the E1B 55-kilodalton protein participates in countering interferon-induced inhibition of adenovirus replication. J Virol 2013; 87:4432–4444 [View Article][PubMed]
    [Google Scholar]
  38. Wright J, Leppard KN. The human adenovirus 5 L4 promoter is activated by cellular stress response protein p53. J Virol 2013; 87:11617–11625 [View Article][PubMed]
    [Google Scholar]
  39. Croft D, Mundo AF, Haw R, Milacic M, Weiser J et al. The reactome pathway knowledgebase. Nucleic Acids Res 2014; 42:D472–D477 [View Article][PubMed]
    [Google Scholar]
  40. Fabregat A, Sidiropoulos K, Garapati P, Gillespie M, Hausmann K et al. The reactome pathway knowledgebase. Nucleic Acids Res 2016; 44:D481–D487 [View Article][PubMed]
    [Google Scholar]
  41. Blackford AN, Grand RJ. Adenovirus E1B 55-kilodalton protein: multiple roles in viral infection and cell transformation. J Virol 2009; 83:4000–4012 [View Article][PubMed]
    [Google Scholar]
  42. Ikeda K, Quertermous T. Molecular isolation and characterization of a soluble isoform of activated leukocyte cell adhesion molecule that modulates endothelial cell function. J Biol Chem 2004; 279:55315–55323 [View Article][PubMed]
    [Google Scholar]
  43. Iolyeva M, Karaman S, Willrodt AH, Weingartner S, Vigl B et al. Novel role for ALCAM in lymphatic network formation and function. FASEB J 2013; 27:978–990 [View Article][PubMed]
    [Google Scholar]
  44. Bartee E, McCormack A, Früh K. Quantitative membrane proteomics reveals new cellular targets of viral immune modulators. PLoS Pathog 2006; 2:e107 [View Article][PubMed]
    [Google Scholar]
  45. Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R et al. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ 1999; 10:629–638[PubMed]
    [Google Scholar]
  46. Lee H, Bennett AM. Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR in cell migration. Mol Cell Biol 2013; 33:1430–1441 [View Article][PubMed]
    [Google Scholar]
  47. Makarov A, Ylivinkka I, Nyman TA, Hyytiäinen M, Keski-Oja J. Ephrin-As, Eph receptors and integrin α3 interact and colocalise at membrane protrusions of U251MG glioblastoma cells. Cell Biol Int 2013; 37:1080–1088 [View Article][PubMed]
    [Google Scholar]
  48. Matthews DA, Russell WC. Adenovirus protein-protein interactions: hexon and protein VI. J Gen Virol 1994; 75:3365–3374 [View Article][PubMed]
    [Google Scholar]
  49. Kanegae Y, Makimura M, Saito I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn J Med Sci Biol 1994; 47:157–166 [View Article][PubMed]
    [Google Scholar]
  50. Blanchette P, Cheng CY, Yan Q, Ketner G, Ornelles DA et al. Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53. Mol Cell Biol 2004; 24:9619–9629 [View Article][PubMed]
    [Google Scholar]
  51. Sarnow P, Sullivan CA, Levine AJ. A monoclonal antibody detecting the adenovirus type 5-E1b-58Kd tumor antigen: characterization of the E1b-58Kd tumor antigen in adenovirus-infected and -transformed cells. Virology 1982; 120:510–517 [View Article][PubMed]
    [Google Scholar]
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