title: Inhibition of mouse TAP by immune evasion molecules encoded by non-murine herpesviruses.
abstract: Herpesviruses escape elimination by cytotoxic T lymphocytes through specific interference with the antigen-presenting function of MHC class I (MHC I) molecules. The transporter associated with antigen processing (TAP) forms a bottleneck in the MHC I antigen presentation pathway. The fact that multiple viruses, especially herpesviruses, encode molecules blocking TAP function is a case in point. The action of these viral immuno evasins is usually potent and very specific, making these proteins valuable tools for studying the cell biology of antigen presentation, including alternative antigen processing pathways. Yet, no dedicated TAP inhibitor has been described for any of the mouse herpesviruses. To permit the use of immuno evasins derived from non-mouse herpesviruses in mouse models, we assessed the cross-species activity of four TAP inhibitors and one tapasin inhibitor in the context of three different mouse haplotypes, H-2(b), H-2(d), and H-2(k). Two of the four TAP inhibitors, the bovine herpesvirus 1-encoded UL49.5 and the human cytomegalovirus (HCMV)-encoded US6 protein, potently inhibited mouse TAP. ICP47 and BNLF2a, encoded by herpes simplexvirus 1 and Epstein-Barr virus, respectively, failed to inhibit TAP in all mouse cells tested. Previous work, however, demonstrated that US6 did not cross the mouse species barrier. We now show that substitution of the cysteine residue at position 108 was responsible for this lack of activity. The HCMV-encoded tapasin inhibitor US3 efficiently downregulated H-2(d) molecules on 3T3 cells, but not in other cell lines tested. Finally, we show that synthetic peptides comprising the functional domain of US6 can be exploited as a versatile TAP inhibitor. In conclusion, a complete overview is presented of the applicability of herpesvirus-encoded TAP and tapasin inhibitors in mouse cells of different genetic background.
authors.affiliation: Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke C
authors.initials: MC
authors.lastname: Verweij
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Wilco
authors.initials: W
authors.lastname: Knetsch
authors.forename: Edwin
authors.initials: E
authors.lastname: Quinten
authors.forename: Anne
authors.initials: A
authors.lastname: Halenius
authors.forename: Nikki
authors.initials: N
authors.lastname: van Bel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hengel
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D003545:Cysteine / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006367:HeLa Cells; D006564:Herpesviridae / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013045:Species Specificity; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; D010455:Peptides; C486171:Tap1 protein, mouse; D014764:Viral Proteins; C107762:tapasin; D007371:Interferon-gamma; D003545:Cysteine