Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP

Danijela Koppers-Lalic, Marieke Verweij, Andrea D. Lipińska, Ying Wang, Edwin Quinten, Eric A. Reits, Joachim Koch, Sandra Loch, Marisa Marcondes Rezende, Franz Daus, Krystyna Bieńkowska-Szewczyk, Nikolaus Osterrieder, Thomas C. Mettenleiter, Mirjam H M Heemskerk, Robert Tampé, Jacques J. Neefjes, Shafiqul I. Chowdhury, Maaike E. Ressing, Frans A M Rijsewijk, Emmanuel J H J Wiertz

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I-restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.

Original languageEnglish (US)
Article numbere1000080
JournalPLoS Pathogens
Volume4
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

Varicellovirus
Equid Herpesvirus 1
Equid Herpesvirus 4
Suid Herpesvirus 1
Bovine Herpesvirus 1
Proteins
Immune Evasion
Histocompatibility Antigens Class I
Peptides
Antigen Presentation
trypsinogen activation peptide
Virus Diseases
Adenosine Triphosphate
Viruses
Cytotoxic T-Lymphocytes
transporter associated with antigen processing (TAP)

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Koppers-Lalic, D., Verweij, M., Lipińska, A. D., Wang, Y., Quinten, E., Reits, E. A., ... Wiertz, E. J. H. J. (2008). Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP. PLoS Pathogens, 4(5), [e1000080]. https://doi.org/10.1371/journal.ppat.1000080

Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP. / Koppers-Lalic, Danijela; Verweij, Marieke; Lipińska, Andrea D.; Wang, Ying; Quinten, Edwin; Reits, Eric A.; Koch, Joachim; Loch, Sandra; Rezende, Marisa Marcondes; Daus, Franz; Bieńkowska-Szewczyk, Krystyna; Osterrieder, Nikolaus; Mettenleiter, Thomas C.; Heemskerk, Mirjam H M; Tampé, Robert; Neefjes, Jacques J.; Chowdhury, Shafiqul I.; Ressing, Maaike E.; Rijsewijk, Frans A M; Wiertz, Emmanuel J H J.

In: PLoS Pathogens, Vol. 4, No. 5, e1000080, 05.2008.

Research output: Contribution to journalArticle

Koppers-Lalic, D, Verweij, M, Lipińska, AD, Wang, Y, Quinten, E, Reits, EA, Koch, J, Loch, S, Rezende, MM, Daus, F, Bieńkowska-Szewczyk, K, Osterrieder, N, Mettenleiter, TC, Heemskerk, MHM, Tampé, R, Neefjes, JJ, Chowdhury, SI, Ressing, ME, Rijsewijk, FAM & Wiertz, EJHJ 2008, 'Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP', PLoS Pathogens, vol. 4, no. 5, e1000080. https://doi.org/10.1371/journal.ppat.1000080
Koppers-Lalic, Danijela ; Verweij, Marieke ; Lipińska, Andrea D. ; Wang, Ying ; Quinten, Edwin ; Reits, Eric A. ; Koch, Joachim ; Loch, Sandra ; Rezende, Marisa Marcondes ; Daus, Franz ; Bieńkowska-Szewczyk, Krystyna ; Osterrieder, Nikolaus ; Mettenleiter, Thomas C. ; Heemskerk, Mirjam H M ; Tampé, Robert ; Neefjes, Jacques J. ; Chowdhury, Shafiqul I. ; Ressing, Maaike E. ; Rijsewijk, Frans A M ; Wiertz, Emmanuel J H J. / Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP. In: PLoS Pathogens. 2008 ; Vol. 4, No. 5.
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abstract = "Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I-restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.",
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AU - Quinten, Edwin

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