Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP.
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 UL 49.5 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 UL 49.5 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 UL 49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL 49.5 proteins block TAP as well, these data indicate that UL 49.5 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 UL 49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL 49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL 49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL 49.5, 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 UL 49.5. Taken together, these results classify the UL 49.5 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.
Koppers-Lalic
Danijela
D
Center of Infectious Diseases and Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.
Verweij
Marieke C
MC
Lipińska
Andrea D
AD
Wang
Ying
Y
Quinten
Edwin
E
Reits
Eric A
EA
Koch
Joachim
J
Loch
Sandra
S
Marcondes Rezende
Marisa
M
Daus
Franz
F
Bieńkowska-Szewczyk
Krystyna
K
Osterrieder
Nikolaus
N
Mettenleiter
Thomas C
TC
Heemskerk
Mirjam H M
MH
Tampé
Robert
R
Neefjes
Jacques J
JJ
Chowdhury
Shafiqul I
SI
Ressing
Maaike E
ME
Rijsewijk
Frans A M
FA
Wiertz
Emmanuel J H J
EJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D004285:Dogs; D007242:Herpesvirus 1, Bovine / Q000235:genetics / Q000276:immunology*; D004861:Herpesvirus 1, Equid / Q000235:genetics / Q000276:immunology*; D011558:Herpesvirus 1, Suid / Q000235:genetics / Q000276:immunology*; D006736:Horses; D006801:Humans; D021381:Protein Transport; D011995:Recombination, Genetic; D013552:Swine; D014161:Transduction, Genetic; D018140:Varicellovirus / Q000472:pathogenicity / Q000502:physiology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
D018528:ATP-Binding Cassette Transporters; C099455:UL49.5 protein, bovine herpesvirus type 1; D014759:Viral Envelope Proteins; C477327:transporter associated with antigen processing (TAP)