Epstein-Barr Viral BNLF2a Protein Hijacks the Tail-anchored Protein Insertion Machinery to Block Antigen Processing by the Transport Complex TAP

• Published in: The Journal of biological chemistry 2011-12, Vol.286 (48), p.41402-41412
• Main Authors: Wycisk, Agnes I., Lin, Jiacheng, Loch, Sandra, Hobohm, Kathleen, Funke, Jessica, Wieneke, Ralph, Koch, Joachim, Skach, William R., Mayerhofer, Peter U., Tampé, Robert
• Format: Article
• Language: English
• Subjects: ABC Transporter; Animals; Antigen Presentation - genetics; Antigen Processing; Arsenite Transporting ATPases - genetics; Arsenite Transporting ATPases - metabolism; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Cellular Immune Response; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - virology; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; Get Pathway; HeLa Cells; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - metabolism; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Immunology; Intracellular Trafficking; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Spodoptera; Tail-anchored Proteins; Viral Immunology; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.237784

Virus-infected cells are eliminated by cytotoxic T lymphocytes, which recognize viral epitopes displayed on major histocompatibility complex class I molecules at the cell surface. Herpesviruses have evolved sophisticated strategies to escape this immune surveillance. During the lytic phase of EBV infection, the viral factor BNLF2a interferes with antigen processing by preventing peptide loading of major histocompatibility complex class I molecules. Here we reveal details of the inhibition mechanism of this EBV protein. We demonstrate that BNLF2a acts as a tail-anchored protein, exploiting the mammalian Asna-1/WRB (Get3/Get1) machinery for posttranslational insertion into the endoplasmic reticulum membrane, where it subsequently blocks antigen translocation by the transporter associated with antigen processing (TAP). BNLF2a binds directly to the core TAP complex arresting the ATP-binding cassette transporter in a transport-incompetent conformation. The inhibition mechanism of EBV BNLF2a is distinct and mutually exclusive of other viral TAP inhibitors. Background: Herpesviruses have evolved sophisticated strategies to escape immune surveillance. Results: EBV BNLF2a acts as tail-anchored protein and is posttranslationally inserted into the ER membrane, where it arrests core TAP in a transport-incompetent conformation. Conclusion: BNLF2a exploits the host tail-anchored protein insertion machinery. Significance: This inhibition mechanism is distinct and mutually exclusive of other viral TAP inhibitors.