title: Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing.
abstract: Detection and elimination of virus-infected cells by cytotoxic T lymphocytes depends on recognition of virus-derived peptides presented by MHC class I molecules. A critical step in this process is the translocation of peptides from the cytoplasm into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Here, we identified the bovine herpesvirus 1-encoded UL49.5 protein as a potent inhibitor of TAP. The expression of UL49.5 results in down-regulation of MHC class I molecules at the cell surface and inhibits detection and lysis of the cells by cytotoxic T lymphocytes. UL49.5 homologs encoded by two other varicelloviruses, pseudorabies-virus and equine herpesvirus 1, also block TAP. Homologs of UL49.5 are widely present in herpesviruses, acting as interaction partners for glycoprotein M, but in several varicelloviruses UL49.5 has uniquely evolved additional functions that mediate its participation in TAP inhibition. Inactivation of TAP by UL49.5 involves two events: inhibition of peptide transport through a conformational arrest of the transporter and degradation of TAP by proteasomes. UL49.5 is degraded along with TAP via a reaction that requires the cytoplasmic tail of UL49.5. Thus, UL49.5 represents a unique immune evasion protein that inactivates TAP through a unique two-tiered process.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
authors.forename: Danijela
authors.initials: D
authors.lastname: Koppers-Lalic
authors.forename: Eric A J
authors.initials: EA
authors.lastname: Reits
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Lipinska
authors.forename: Rupert
authors.initials: R
authors.lastname: Abele
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
authors.forename: Marisa
authors.initials: M
authors.lastname: Marcondes Rezende
authors.forename: Pieter
authors.initials: P
authors.lastname: Admiraal
authors.forename: Daphne
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: Krystyna
authors.initials: K
authors.lastname: Bienkowska-Szewczyk
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Mettenleiter
authors.forename: Frans A M
authors.initials: FA
authors.lastname: Rijsewijk
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018140:Varicellovirus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D011993:Recombinant Fusion Proteins; C073119:TAP1 protein, human; C099455:UL49.5 protein, bovine herpesvirus type 1; D014759:Viral Envelope Proteins; C071692:TAP2 protein, human; D000255:Adenosine Triphosphate; D046988:Proteasome Endopeptidase Complex