Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses

Marieke Verweij, Andrea D. Lipińska, Danijela Koppers-Lalic, Edwin Quinten, Jessica Funke, Hans C. van Leeuwen, Krystyna Bieńkowska-Szewczyk, Joachim Koch, Maaike E. Ressing, Emmanuel J H J Wiertz

Research output: Contribution to journalArticle

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Abstract

Viral infections are counteracted by virus-specific cytotoxic T cells that recognize the infected cell via MHC class I (MHC I) molecules presenting virus-derived peptides. The loading of the peptides onto MHC I molecules occurs in the endoplasmic reticulum (ER) and is facilitated by the peptide loading complex. A key player in this complex is the transporter associated with antigen processing (TAP), which translocates the viral peptides from the cytosol into the ER. Herpesviruses have developed many strategies to evade cytotoxic T cells. Several members of the genus Varicellovirus encode a UL49.5 protein that prevents peptide transport through TAP. These include bovine herpesvirus (BoHV) 1, BoHV-5, bubaline herpesvirus 1, cervid herpesvirus 1, pseudorabies virus, felid herpesvirus 1, and equine herpesvirus 1 and 4. BoHV-1 UL49.5 inhibits TAP by preventing conformational changes essential for peptide transport and by inducing degradation of the TAP complex. UL49.5 consists of an ER luminal N-terminal domain, a transmembrane domain and a cytosolic C-terminal tail domain.In this study, the following features of UL49.5 were deciphered: (1) chimeric constructs of BoHV-1 and VZV UL49.5 attribute the lack of TAP inhibition by VZV UL49.5 to its ER-luminal domain, (2) the ER-luminal and TM domains of UL49.5 are required for efficient interaction with and inhibition of TAP, (3) the C-terminal RXRX sequence is essential for TAP degradation by BoHV-1 UL49.5, and (4) in addition to the RXRX sequence, the cytoplasmic tail of BoHV-1 UL49.5 carries a motif that is required for efficient TAP inhibition by the protein. A model is presented depicting how the different domains of UL49.5 may block the translocation of peptides by TAP and target TAP for proteasomal degradation.

Original languageEnglish (US)
Pages (from-to)2038-2051
Number of pages14
JournalMolecular Immunology
Volume48
Issue number15-16
DOIs
StatePublished - Sep 2011

Fingerprint

Varicellovirus
Bovine Herpesvirus 1
Endoplasmic Reticulum
Herpesviridae
Peptides
Proteins
trypsinogen activation peptide
Bovine Herpesvirus 5
Equid Herpesvirus 4
Equid Herpesvirus 1
Viruses
Suid Herpesvirus 1
T-Lymphocytes
Virus Diseases
Cytosol

Keywords

  • Antigen presentation
  • Herpesviruses
  • Immune evasion
  • MHC class I

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

Verweij, M., Lipińska, A. D., Koppers-Lalic, D., Quinten, E., Funke, J., van Leeuwen, H. C., ... Wiertz, E. J. H. J. (2011). Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses. Molecular Immunology, 48(15-16), 2038-2051. https://doi.org/10.1016/j.molimm.2011.06.438

Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses. / Verweij, Marieke; Lipińska, Andrea D.; Koppers-Lalic, Danijela; Quinten, Edwin; Funke, Jessica; van Leeuwen, Hans C.; Bieńkowska-Szewczyk, Krystyna; Koch, Joachim; Ressing, Maaike E.; Wiertz, Emmanuel J H J.

In: Molecular Immunology, Vol. 48, No. 15-16, 09.2011, p. 2038-2051.

Research output: Contribution to journalArticle

Verweij, M, Lipińska, AD, Koppers-Lalic, D, Quinten, E, Funke, J, van Leeuwen, HC, Bieńkowska-Szewczyk, K, Koch, J, Ressing, ME & Wiertz, EJHJ 2011, 'Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses', Molecular Immunology, vol. 48, no. 15-16, pp. 2038-2051. https://doi.org/10.1016/j.molimm.2011.06.438
Verweij M, Lipińska AD, Koppers-Lalic D, Quinten E, Funke J, van Leeuwen HC et al. Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses. Molecular Immunology. 2011 Sep;48(15-16):2038-2051. https://doi.org/10.1016/j.molimm.2011.06.438
Verweij, Marieke ; Lipińska, Andrea D. ; Koppers-Lalic, Danijela ; Quinten, Edwin ; Funke, Jessica ; van Leeuwen, Hans C. ; Bieńkowska-Szewczyk, Krystyna ; Koch, Joachim ; Ressing, Maaike E. ; Wiertz, Emmanuel J H J. / Structural and functional analysis of the TAP-inhibiting UL49.5 proteins of varicelloviruses. In: Molecular Immunology. 2011 ; Vol. 48, No. 15-16. pp. 2038-2051.
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