Varicellovirus UL49.5 Proteins Differentially Affect the Function of the Transporter Associated with Antigen Processing, TAP

PLoS Pathogens

Marisa Marcondes Rezende¹  Danijela Koppers-Lalic¹  Marieke C. Verweij¹  Frans A. M. Rijsewijk¹  Edwin Quinten¹  Eric A. Reits²  Maaike E. Ressing³  Ying Wang³  Robert Tampé⁴  Nikolaus Osterrieder⁵  Krystyna Bieńkowska-Szewczyk⁶  Andrea D. Lipińska⁶  Shafiqul I. Chowdhury⁷  Thomas C. Mettenleiter⁸  Jacques J. Neefjes⁹  Joachim Koch⁹  Sandra Loch⁹  Mirjam H. M. Heemskerk^1,10  Emmanuel J. H. J. Wiertz^1,11  Franz Daus^1,11 

[1] Center of Infectious Diseases and Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands;Department of Cell Biology and Histology, Academic Medical Centre, Amsterdam, The Netherlands;Department of Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America;Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands;Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America;Department of Molecular Virology, University of Gdańsk, Gdańsk, Poland;Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Institute for Virology, Berlin, Germany;Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Frankfurt/Main, Germany;Institute of Molecular Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany;Virus Discovery Unit, ASG-Lelystad, Lelystad, The Netherlands

关键词: Antigen presentation;    Major histocompatibility complex;    MHC class I genes;    Transport inhibition assay;    Herpesviruses;    Equines;    T cells;    Immunoblotting;   

DOI  :  10.1371/journal.ppat.1000080

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY