title: Epstein-Barr viral BNLF2a protein hijacks the tail-anchored protein insertion machinery to block antigen processing by the transport complex TAP.
abstract: 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.
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Agnes I
authors: AI
authors: Wycisk
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Jiacheng
authors: J
authors: Lin
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Sandra
authors: S
authors: Loch
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Kathleen
authors: K
authors: Hobohm
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Jessica
authors: J
authors: Funke
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Ralph
authors: R
authors: Wieneke
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Joachim
authors: J
authors: Koch
authors: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: William R
authors: WR
authors: Skach
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany.
authors: Peter U
authors: PU
authors: Mayerhofer
authors: Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Max-von-Laue Str. 9, 60438 Frankfurt, Germany. Electronic address: tampe@em.uni-frankfurt.de.
authors: Robert
authors: R
authors: Tampé
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D053501:Arsenite Transporting ATPases / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018411:Spodoptera; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C539239:BNLF21 protein, human herpesvirus 4; C111546:GET1 protein, human; C489667:GET3 protein, human; D015395:Histocompatibility Antigens Class I; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014763:Viral Matrix Proteins; C477327:transporter associated with antigen processing (TAP); D053501:Arsenite Transporting ATPases