1887

Journal of General Virology header logo

Volume 98, Issue 12

Vaccinia virus protein A49 activates Wnt signalling by targetting the E3 ligase β-TrCP Open Access

Abstract

Vaccinia virus (VACV) encodes multiple proteins inhibiting the NF-κB signalling pathway. One of these, A49, targets the E3 ubiquitin ligase β-TrCP, which is responsible for the ubiquitylation and consequential proteosomal degradation of IκBα and the release of the NF-κB heterodimer. β-TrCP is a pleiotropic enzyme ubiquitylating multiple cellular substrates, including the transcriptional activator β-catenin. Here we demonstrate that A49 can activate the Wnt signalling pathway, a critical pathway that is involved in cell cycle and cell differentiation, and is controlled by β-catenin. The data presented show that the expression of A49 ectopically or during VACV infection causes accumulation of β-catenin, and that A49 triggering of Wnt signalling is dependent on binding β-TrCP. This is consistent with A49 blocking the ability of β-TrCP to recognise β-catenin and IκBα, and possibly other cellular targets. Thus, A49 targetting of β-TrCP affects multiple cellular pathways, including the NF-κB and Wnt signalling cascades.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): protein A49 , vaccinia virus , Wnt pathway , β-catenin and β-transducin repeat containing protein
© 2017 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000946
2017-12-01
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/12/3086.html?itemId=/content/journal/jgv/10.1099/jgv.0.000946&mimeType=html&fmt=ahah

References

  1. Alcami A. Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol 2003; 3:36–50 [View Article][PubMed]
     [Google Scholar]
  2. Smith GL, Benfield CT, Maluquer de Motes C, Mazzon M, Ember SW et al. Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 2013; 94:2367–2392 [View Article][PubMed]
     [Google Scholar]
  3. Veyer DL, Carrara G, Maluquer de Motes C, Smith GL. Vaccinia virus evasion of regulated cell death. Immunol Lett 2017; 186:68–80 [View Article][PubMed]
     [Google Scholar]
  4. Mazzon M, Castro C, Roberts LD, Griffin JL, Smith GL. A role for vaccinia virus protein C16 in reprogramming cellular energy metabolism. J Gen Virol 2015; 96:395–407 [View Article][PubMed]
     [Google Scholar]
  5. Mazzon M, Peters NE, Loenarz C, Krysztofinska EM, Ember SW et al. A mechanism for induction of a hypoxic response by vaccinia virus. Proc Natl Acad Sci USA 2013; 110:12444–12449 [View Article][PubMed]
     [Google Scholar]
  6. Peters NE, Ferguson BJ, Mazzon M, Fahy AS, Krysztofinska E et al. A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus. PLoS Pathog 2013; 9:e1003649 [View Article][PubMed]
     [Google Scholar]
  7. Cooray S, Bahar MW, Abrescia NG, McVey CE, Bartlett NW et al. Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein. J Gen Virol 2007; 88:1656–1666 [View Article][PubMed]
     [Google Scholar]
  8. Maluquer de Motes C, Cooray S, Ren H, Almeida GM, McGourty K et al. Inhibition of apoptosis and NF-κB activation by vaccinia protein N1 occur via distinct binding surfaces and make different contributions to virulence. PLoS Pathog 2011; 7:e1002430 [View Article][PubMed]
     [Google Scholar]
  9. Ren H, Ferguson BJ, Maluquer de Motes C, Sumner RP, Harman LE et al. Enhancement of CD8(+) T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor. Immunology 2015; 145:34–49 [View Article][PubMed]
     [Google Scholar]
  10. Maluquer de Motes C, Schiffner T, Sumner RP, Smith GL. Vaccinia virus virulence factor N1 can be ubiquitylated on multiple lysine residues. J Gen Virol 2014; 95:2038–2049 [View Article][PubMed]
     [Google Scholar]
  11. Gerlic M, Faustin B, Postigo A, Yu EC, Proell M et al. Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation. Proc Natl Acad Sci USA 2013; 110:7808–7813 [View Article][PubMed]
     [Google Scholar]
  12. Postigo A, Cross JR, Downward J, Way M. Interaction of F1L with the BH3 domain of Bak is responsible for inhibiting vaccinia-induced apoptosis. Cell Death Differ 2006; 13:1651–1662 [View Article][PubMed]
     [Google Scholar]
  13. Wasilenko ST, Banadyga L, Bond D, Barry M. The vaccinia virus F1L protein interacts with the proapoptotic protein Bak and inhibits Bak activation. J Virol 2005; 79:14031–14043 [View Article][PubMed]
     [Google Scholar]
  14. Wasilenko ST, Stewart TL, Meyers AF, Barry M. Vaccinia virus encodes a previously uncharacterized mitochondrial-associated inhibitor of apoptosis. Proc Natl Acad Sci USA 2003; 100:14345–14350 [View Article][PubMed]
     [Google Scholar]
  15. Veyer DL, Maluquer de Motes C, Sumner RP, Ludwig L, Johnson BF et al. Analysis of the anti-apoptotic activity of four vaccinia virus proteins demonstrates that B13 is the most potent inhibitor in isolation and during viral infection. J Gen Virol 2014; 95:2757–2768 [View Article][PubMed]
     [Google Scholar]
  16. Postigo A, Way M. The vaccinia virus-encoded Bcl-2 homologues do not act as direct Bax inhibitors. J Virol 2012; 86:203–213 [View Article][PubMed]
     [Google Scholar]
  17. Mansur DS, Maluquer de Motes C, Unterholzner L, Sumner RP, Ferguson BJ et al. Poxvirus targeting of E3 ligase β-TrCP by molecular mimicry: a mechanism to inhibit NF-κB activation and promote immune evasion and virulence. PLoS Pathog 2013; 9:e1003183 [View Article][PubMed]
     [Google Scholar]
  18. Neidel S, Maluquer de Motes C, Mansur DS, Strnadova P, Smith GL et al. Vaccinia virus protein A49 is an unexpected member of the B-cell Lymphoma (Bcl)-2 protein family. J Biol Chem 2015; 290:5991–6002 [View Article][PubMed]
     [Google Scholar]
  19. Graham SC, Bahar MW, Cooray S, Chen RA, Whalen DM et al. Vaccinia virus proteins A52 and B14 Share a Bcl-2-like fold but have evolved to inhibit NF-κB rather than apoptosis. PLoS Pathog 2008; 4:e1000128 [View Article][PubMed]
     [Google Scholar]
  20. Kanarek N, Ben-Neriah Y. Regulation of NF-κB by ubiquitination and degradation of the IκBs. Immunol Rev 2012; 246:77–94 [View Article][PubMed]
     [Google Scholar]
  21. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A et al. Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1995; 92:10599–10603 [View Article][PubMed]
     [Google Scholar]
  22. Yaron A, Gonen H, Alkalay I, Hatzubai A, Jung S et al. Inhibition of NF-κB cellular function via specific targeting of the IκB-ubiquitin ligase. Embo J 1997; 16:6486–6494 [View Article][PubMed]
     [Google Scholar]
  23. Frescas D, Pagano M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat Rev Cancer 2008; 8:438–449 [View Article][PubMed]
     [Google Scholar]
  24. Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 2012; 149:1192–1205 [View Article][PubMed]
     [Google Scholar]
  25. Parkinson JE, Smith GL. Vaccinia virus gene A36R encodes a Mr 43-50 K protein on the surface of extracellular enveloped virus. Virology 1994; 204:376–390 [View Article][PubMed]
     [Google Scholar]
  26. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 1997; 275:1787–1790 [View Article][PubMed]
     [Google Scholar]
  27. Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z et al. High-throughput mapping of a dynamic signaling network in mammalian cells. Science 2005; 307:1621–1625 [View Article][PubMed]
     [Google Scholar]
  28. Unterholzner L, Sumner RP, Baran M, Ren H, Mansur DS et al. Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7. PLoS Pathog 2011; 7:e1002247 [View Article][PubMed]
     [Google Scholar]
  29. Margottin F, Bour SP, Durand H, Selig L, Benichou S et al. A novel human WD protein, h-βTrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol Cell 1998; 1:565–574 [View Article][PubMed]
     [Google Scholar]
  30. Sumner RP, Maluquer de Motes C, Veyer DL, Smith GL. Vaccinia virus inhibits NF-κB-dependent gene expression downstream of p65 translocation. J Virol 2014; 88:3092–3102 [View Article][PubMed]
     [Google Scholar]
  31. van Zuylen WJ, Rawlinson WD, Ford CE. The Wnt pathway: a key network in cell signalling dysregulated by viruses. Rev Med Virol 2016; 26:340–355 [View Article][PubMed]
     [Google Scholar]
  32. Angelova M, Zwezdaryk K, Ferris M, Shan B, Morris CA et al. Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway. PLoS Pathog 2012; 8:e1002959 [View Article][PubMed]
     [Google Scholar]
  33. Dingwell KS, Johnson DC. The herpes simplex virus gE-gI complex facilitates cell-to-cell spread and binds to components of cell junctions. J Virol 1998; 72:8933–8942[PubMed]
     [Google Scholar]
  34. Langemeijer EV, Slinger E, de Munnik S, Schreiber A, Maussang D et al. Constitutive β-catenin signaling by the viral chemokine receptor US28. PLoS One 2012; 7:e48935 [View Article][PubMed]
     [Google Scholar]
  35. Tang W, Pavlish OA, Spiegelman VS, Parkhitko AA, Fuchs SY. Interaction of Epstein-Barr virus latent membrane protein 1 with SCFHOS/β-TrCP E3 ubiquitin ligase regulates extent of NF-κB activation. J Biol Chem 2003; 278:48942–48949 [View Article][PubMed]
     [Google Scholar]
  36. You S, Zhang F, Meng F, Li H, Liu Q et al. EBV-encoded LMP1 increases nuclear β-catenin accumulation and its transcriptional activity in nasopharyngeal carcinoma. Tumour Biol 2011; 32:623–630 [View Article][PubMed]
     [Google Scholar]
  37. Yang P, An H, Liu X, Wen M, Zheng Y et al. The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway. Nat Immunol 2010; 11:487–494 [View Article][PubMed]
     [Google Scholar]
  38. Khan KA, do F, Marineau A, Doyon P, Clément JF et al. Fine-tuning of the RIG-I-like receptor/interferon regulatory factor 3-dependent antiviral innate immune response by the glycogen synthase kinase 3/β-catenin pathway. Mol Cell Biol 2015; 35:3029–3043 [View Article][PubMed]
     [Google Scholar]
  39. Zhu J, Coyne CB, Sarkar SN. PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin. Embo J 2011; 30:4838–4849 [View Article][PubMed]
     [Google Scholar]
  40. Hillesheim A, Nordhoff C, Boergeling Y, Ludwig S, Wixler V. β-catenin promotes the type I IFN synthesis and the IFN-dependent signaling response but is suppressed by influenza A virus-induced RIG-I/NF-κB signaling. Cell Commun Signal 2014; 12:29 [View Article][PubMed]
     [Google Scholar]
  41. Lei CQ, Zhong B, Zhang Y, Zhang J, Wang S et al. Glycogen synthase kinase 3β regulates IRF3 transcription factor-mediated antiviral response via activation of the kinase TBK1. Immunity 2010; 33:878–889 [View Article][PubMed]
     [Google Scholar]
  42. Baril M, Es-Saad S, Chatel-Chaix L, Fink K, Pham T et al. Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses. PLoS Pathog 2013; 9:e1003416 [View Article][PubMed]
     [Google Scholar]
  43. Harmon B, Bird SW, Schudel BR, Hatch AV, Rasley A et al. A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during rift valley fever virus infection. J Virol 2016; 90:7084–7097 [View Article][PubMed]
     [Google Scholar]
  44. Smith JL, Jeng S, McWeeney SK, Hirsch AJ. A microRNA screen identifies the Wnt signaling pathway as a regulator of the interferon response during flavivirus infection. J Virol 2017; 91:e02388-16 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000946
Loading
Vaccinia virus protein A49 activates Wnt signalling by targetting the E3 ligase β-TrCP
J. Gen. Virol. 98, 3086 (2017); https://doi.org/10.1099/jgv.0.000946
/content/journal/jgv/10.1099/jgv.0.000946
/content/journal/jgv/10.1099/jgv.0.000946
Loading

Data & Media loading...

Most cited Most Cited RSS feed

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