Epstein-Barr viral BNLF2a protein hijacks the tail-anchored protein insertion machinery to block antigen processing by the transport complex TAP

J Biol Chem. 2011 Dec 2;286(48):41402-41412. doi: 10.1074/jbc.M111.237784. Epub 2011 Oct 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antigen Presentation / genetics
  • Arsenite Transporting ATPases / genetics
  • Arsenite Transporting ATPases / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / virology
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / metabolism*
  • HeLa Cells
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / metabolism*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Spodoptera
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*

Substances

  • ATP-Binding Cassette Transporters
  • BNLF21 protein, human herpesvirus 4
  • GET1 protein, human
  • GET3 protein, human
  • Histocompatibility Antigens Class I
  • Multiprotein Complexes
  • Nuclear Proteins
  • Viral Matrix Proteins
  • transporter associated with antigen processing (TAP)
  • Arsenite Transporting ATPases