1887

Abstract

Mature dendritic cells (mDCs) are the most potent antigen-presenting cells known today, as they are the only antigen-presenting cells able to induce naïve T-cells. Therefore, they play a crucial role during the induction of effective antiviral immune responses. Interestingly, the surface molecule CD83 expressed on mDCs is targeted by several viruses. As CD83 has been shown to exert co-stimulatory functions on mDCs, its downmodulation represents a viral immune escape mechanism. Mechanistically, it has been shown that herpes simplex virus type 1 infection leads to proteasomal degradation of CD83, resulting in a strongly diminished T-cell stimulatory capacity of the infected mDC. Previous data suggest that the viral immediate-early protein ICP0 (infected-cell protein 0) plays an important role in this process. In the present study, we showed that ICP0 is sufficient to induce CD83 degradation in the absence of any other viral factor. However, the mechanism of ICP0-mediated CD83 degradation is not yet understood. Here, we provide evidence that ubiquitination of lysine residues is, despite the published E3 ubiquitin ligase activity of ICP0, not necessary for CD83 degradation. This finding was underlined by the observation that expression of an ICP0 mutant lacking the E3 ubiquitin ligase domain in mDCs still induced CD83 degradation. Finally, inhibition of E1 activating enzyme using the specific inhibitor 4[4-(5-nitro-furan-2-ylmethylene)-3.5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester did not prevent CD83 degradation. Taken together, our data provide strong evidence that ICP0 alone induces CD83 degradation independent of its E3 ubiquitin ligase function and of the ubiquitin machinery.

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2014-06-01
2024-03-28
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References

  1. Aerts-Toegaert C., Heirman C., Tuyaerts S., Corthals J., Aerts J. L., Bonehill A., Thielemans K., Breckpot K. 2007; CD83 expression on dendritic cells and T cells: correlation with effective immune responses. Eur J Immunol 37:686–695 [View Article][PubMed]
    [Google Scholar]
  2. Anandasabapathy N., Ford G. S., Bloom D., Holness C., Paragas V., Seroogy C., Skrenta H., Hollenhorst M., Fathman C. G., Soares L. 2003; GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18:535–547 [View Article][PubMed]
    [Google Scholar]
  3. Banchereau J., Steinman R. M. 1998; Dendritic cells and the control of immunity. Nature 392:245–252 [View Article][PubMed]
    [Google Scholar]
  4. Bock F., Rössner S., Onderka J., Lechmann M., Pallotta M. T., Fallarino F., Boon L., Nicolette C., DeBenedette M. A. other authors 2013; Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival. J Immunol 191:1965–1975 [View Article][PubMed]
    [Google Scholar]
  5. Boutell C., Sadis S., Everett R. D. 2002; Herpes simplex virus type 1 immediate-early protein ICP0 and is isolated RING finger domain act as ubiquitin E3 ligases in vitro. J Virol 76:841–850 [View Article][PubMed]
    [Google Scholar]
  6. Breitschopf K., Bengal E., Ziv T., Admon A., Ciechanover A. 1998; A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein. EMBO J 17:5964–5973 [View Article][PubMed]
    [Google Scholar]
  7. Coffin R. S., MacLean A. R., Latchman D. S., Brown S. M. 1996; Gene delivery to the central and peripheral nervous systems of mice using HSV1 ICP34.5 deletion mutant vectors. Gene Ther 3:886–891[PubMed]
    [Google Scholar]
  8. Erales J., Coffino P. 2014; Ubiquitin-independent proteasomal degradation. Biochim Biophys Acta 1843:216–221 [View Article][PubMed]
    [Google Scholar]
  9. Everett R. D. 2000; ICP0, a regulator of herpes simplex virus during lytic and latent infection. BioEssays 22:761–770 [View Article][PubMed]
    [Google Scholar]
  10. Everett R. D., Preston C. M., Stow N. D. 1991; Functional and genetic analysis of the role of Vmw110 in herpes simplex virus replication. pp. 50–76 In Herpes Virus Transcription and its Regulation Edited by Wagner E. K. Boca Raton, FL: CRC Press;
    [Google Scholar]
  11. Everett R. D., Freemont P., Saitoh H., Dasso M., Orr A., Kathoria M., Parkinson J. 1998; The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110- and proteasome-dependent loss of several PML isoforms. J Virol 72:6581–6591[PubMed]
    [Google Scholar]
  12. Everett R. D., Boutell C., Orr A. 2004; Phenotype of a herpes simplex virus type 1 mutant that fails to express immediate-early regulatory protein ICP0. J Virol 78:1763–1774 [View Article][PubMed]
    [Google Scholar]
  13. Everett R. D., Rechter S., Papior P., Tavalai N., Stamminger T., Orr A. 2006; PML contributes to a cellular mechanism of repression of herpes simplex virus type 1 infection that is inactivated by ICP0. J Virol 80:7995–8005 [View Article][PubMed]
    [Google Scholar]
  14. Fujimoto Y., Tu L., Miller A. S., Bock C., Fujimoto M., Doyle C., Steeber D. A., Tedder T. F. 2002; CD83 expression influences CD4+ T cell development in the thymus. Cell 108:755–767 [View Article][PubMed]
    [Google Scholar]
  15. Ge W., Arp J., Lian D., Liu W., Baroja M. L., Jiang J., Ramcharran S., Eldeen F. Z., Zinser E. other authors 2010; Immunosuppression involving soluble CD83 induces tolerogenic dendritic cells that prevent cardiac allograft rejection. Transplantation 90:1145–1156 [View Article][PubMed]
    [Google Scholar]
  16. Glickman M. H., Ciechanover A. 2002; The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428[PubMed]
    [Google Scholar]
  17. Gu H., Roizman B. 2003; The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a. Proc Natl Acad Sci U S A 100:8963–8968 [View Article][PubMed]
    [Google Scholar]
  18. Hagglund R., Roizman B. 2004; Role of ICP0 in the strategy of conquest of the host cell by herpes simplex virus 1. J Virol 78:2169–2178 [View Article][PubMed]
    [Google Scholar]
  19. Hock B. D., Kato M., McKenzie J. L., Hart D. N. 2001; A soluble form of CD83 is released from activated dendritic cells and B lymphocytes, and is detectable in normal human sera. Int Immunol 13:959–967 [View Article][PubMed]
    [Google Scholar]
  20. Hock B. D., Haring L. F., Steinkasserer A., Taylor K. G., Patton W. N., McKenzie J. L. 2004; The soluble form of CD83 is present at elevated levels in a number of hematological malignancies. Leuk Res 28:237–241 [View Article][PubMed]
    [Google Scholar]
  21. Hwang J., Kalejta R. F. 2007; Proteasome-dependent, ubiquitin-independent degradation of Daxx by the viral pp71 protein in human cytomegalovirus-infected cells. Virology 367:334–338 [View Article][PubMed]
    [Google Scholar]
  22. Kalejta R. F., Shenk T. 2003; Proteasome-dependent, ubiquitin-independent degradation of the Rb family of tumor suppressors by the human cytomegalovirus pp71 protein. Proc Natl Acad Sci U S A 100:3263–3268 [View Article][PubMed]
    [Google Scholar]
  23. Klein E., Koch S., Borm B., Neumann J., Herzog V., Koch N., Bieber T. 2005; CD83 localization in a recycling compartment of immature human monocyte-derived dendritic cells. Int Immunol 17:477–487 [View Article][PubMed]
    [Google Scholar]
  24. Kruse M., Rosorius O., Krätzer F., Stelz G., Kuhnt C., Schuler G., Hauber J., Steinkasserer A. 2000; Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J Virol 74:7127–7136 [View Article][PubMed]
    [Google Scholar]
  25. Kummer M., Turza N. M., Muhl-Zurbes P., Lechmann M., Boutell C., Coffin R. S., Everett R. D., Steinkasserer A., Prechtel A. T. 2007; Herpes simplex virus type 1 induces CD83 degradation in mature dendritic cells with immediate-early kinetics via the cellular proteasome. J Virol 81:6326–6338 [View Article][PubMed]
    [Google Scholar]
  26. Lan Z., Lian D., Liu W., Arp J., Charlton B., Ge W., Brand S., Healey D., DeBenedette M. other authors 2010; Prevention of chronic renal allograft rejection by soluble CD83. Transplantation 90:1278–1285 [View Article][PubMed]
    [Google Scholar]
  27. Lees-Miller S. P., Long M. C., Kilvert M. A., Lam V., Rice S. A., Spencer C. A. 1996; Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0. J Virol 70:7471–7477[PubMed]
    [Google Scholar]
  28. Lomonte P., Everett R. D. 1999; Herpes simplex virus type 1 immediate-early protein Vmw110 inhibits progression of cells through mitosis and from G1 into S phase of the cell cycle. J Virol 73:9456–9467[PubMed]
    [Google Scholar]
  29. Lomonte P., Sullivan K. F., Everett R. D. 2001; Degradation of nucleosome-associated centromeric histone H3-like protein CENP-A induced by herpes simplex virus type 1 protein ICP0. J Biol Chem 276:5829–5835 [View Article][PubMed]
    [Google Scholar]
  30. Lorick K. L., Jensen J. P., Fang S., Ong A. M., Hatakeyama S., Weissman A. M. 1999; RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96:11364–11369 [View Article][PubMed]
    [Google Scholar]
  31. Maul G. G., Everett R. D. 1994; The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0. J Gen Virol 75:1223–1233 [View Article][PubMed]
    [Google Scholar]
  32. Morrow G., Slobedman B., Cunningham A. L., Abendroth A. 2003; Varicella-zoster virus productively infects mature dendritic cells and alters their immune function. J Virol 77:4950–4959 [View Article][PubMed]
    [Google Scholar]
  33. Parkinson J., Lees-Miller S. P., Everett R. D. 1999; Herpes simplex virus type 1 immediate-early protein Vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase. J Virol 73:650–657[PubMed]
    [Google Scholar]
  34. Prechtel A. T., Turza N. M., Theodoridis A. A., Steinkasserer A. 2007; CD83 knockdown in monocyte-derived dendritic cells by small interfering RNA leads to a diminished T cell stimulation. J Immunol 178:5454–5464[PubMed] [CrossRef]
    [Google Scholar]
  35. Reinwald S., Wiethe C., Westendorf A. M., Breloer M., Probst-Kepper M., Fleischer B., Steinkasserer A., Buer J., Hansen W. 2008; CD83 expression in CD4+ T cells modulates inflammation and autoimmunity. J Immunol 180:5890–5897[PubMed] [CrossRef]
    [Google Scholar]
  36. Samady L., Costigliola E., MacCormac L., McGrath Y., Cleverley S., Lilley C. E., Smith J., Latchman D. S., Chain B., Coffin R. S. 2003; Deletion of the virion host shutoff protein (vhs) from herpes simplex virus (HSV) relieves the viral block to dendritic cell activation: potential of vhs HSV vectors for dendritic cell-mediated immunotherapy. J Virol 77:3768–3776 [View Article][PubMed]
    [Google Scholar]
  37. Schmidtke G., Aichem A., Groettrup M. 2014; FAT10ylation as a signal for proteasomal degradation. Biochim Biophys Acta 1843:97–102 [View Article][PubMed]
    [Google Scholar]
  38. Sdek P., Ying H., Chang D. L. F., Qiu W., Zheng H., Touitou R., Allday M. J., Xiao Z.-X. 2005; MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell 20:699–708 [View Article][PubMed]
    [Google Scholar]
  39. Sénéchal B., Boruchov A. M., Reagan J. L., Hart D. N., Young J. W. 2004; Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103:4207–4215 [View Article][PubMed]
    [Google Scholar]
  40. Setz C., Friedrich M., Hahn S., Dörrie J., Schaft N., Schuler G., Schubert U. 2013; Just one position-independent lysine residue can direct MelanA into proteasomal degradation following N-terminal fusion of ubiquitin. PLoS ONE 8:e55567 [View Article][PubMed]
    [Google Scholar]
  41. Singh Gautam A. K., Balakrishnan S., Venkatraman P. 2012; Direct ubiquitin independent recognition and degradation of a folded protein by the eukaryotic proteasomes-origin of intrinsic degradation signals. PLoS ONE 7:e34864 [View Article][PubMed]
    [Google Scholar]
  42. Sodeik B., Ebersold M. W., Helenius A. 1997; Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus. J Cell Biol 136:1007–1021 [View Article][PubMed]
    [Google Scholar]
  43. Su L. L., Iwai H., Lin J. T., Fathman C. G. 2009; The transmembrane E3 ligase GRAIL ubiquitinates and degrades CD83 on CD4 T cells. J Immunol 183:438–444 [View Article][PubMed]
    [Google Scholar]
  44. Uhde M., Kuehl S., Richardt U., Fleischer B., Osterloh A. 2013; Differential regulation of marginal zone and follicular B cell responses by CD83. Int Immunol 25:507–520 [View Article][PubMed]
    [Google Scholar]
  45. Van Sant C., Hagglund R., Lopez P., Roizman B. 2001; The infected cell protein 0 of herpes simplex virus 1 dynamically interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin-conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A 98:8815–8820 [View Article][PubMed]
    [Google Scholar]
  46. Whitley R. J., Roizman B. 2001; Herpes simplex virus infections. Lancet 357:1513–1518 [View Article][PubMed]
    [Google Scholar]
  47. Winkler L. L., Hwang J., Kalejta R. F. 2013; Ubiquitin-independent proteasomal degradation of tumor suppressors by human cytomegalovirus pp71 requires the 19S regulatory particle. J Virol 87:4665–4671 [View Article][PubMed]
    [Google Scholar]
  48. Wolenski M., Cramer S. O., Ehrlich S., Steeg C., Fleischer B., von Bonin A. 2003; Enhanced activation of CD83-positive T cells. Scand J Immunol 58:306–311 [View Article][PubMed]
    [Google Scholar]
  49. Yang Y., Kitagaki J., Dai R. M., Tsai Y. C., Lorick K. L., Ludwig R. L., Pierre S. A., Jensen J. P., Davydov I. V. other authors 2007; Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer Res 67:9472–9481 [View Article][PubMed]
    [Google Scholar]
  50. Zhou L. J., Tedder T. F. 1996; CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A 93:2588–2592 [View Article][PubMed]
    [Google Scholar]
  51. Zinser E., Lechmann M., Golka A., Lutz M. B., Steinkasserer A. 2004; Prevention and treatment of experimental autoimmune encephalomyelitis by soluble CD83. J Exp Med 200:345–351 [View Article][PubMed]
    [Google Scholar]
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