A Viral Inhibitor of Peptide Transporters for Antigen Presentation

Nature. 1995 Jun 1;375(6530):415-8. doi: 10.1038/375415a0.

Abstract

Cytotoxic T lymphocytes lyse target cells after T-cell-receptor-mediated recognition of class I major histocompatibility complex molecules presenting peptides. Antigenic peptides are generated in the cytoplasm by proteasomes and translocated into the lumen of the endoplasmic reticulum (ER) by peptide transporters (TAP). Herpes simplex virus (HSV) expresses a cytoplasmic protein, ICP47, which seems to interfere with such immune surveillance by mediating retention of 'empty' class I molecules in the ER. By expressing ICP47 in HeLa cells under an inducible promoter, we show that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides. This inhibition was overcome by transfecting murine TAP. Further, we demonstrate that ICP47 colocalizes and physically associates with TAP within the cell. Inhibition of peptide translocation by a viral protein indicates a previously undocumented potential mechanism for viral immune evasion.

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / metabolism
  • Amino Acid Sequence
  • Animals
  • Antigen Presentation*
  • Biological Transport / drug effects
  • Endoplasmic Reticulum / metabolism
  • HeLa Cells
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / physiology*
  • Interferon-gamma / pharmacology
  • Mice
  • Molecular Sequence Data
  • Precipitin Tests
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Simplexvirus / immunology*
  • Simplexvirus / physiology
  • Tetracyclines / pharmacology

Substances

  • ATP-Binding Cassette Transporters
  • Histocompatibility Antigens Class I
  • Immediate-Early Proteins
  • Recombinant Proteins
  • Tetracyclines
  • Interferon-gamma