Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus

J Immunol. 2010 Jul 15;185(2):1093-102. doi: 10.4049/jimmunol.1000789. Epub 2010 Jun 7.

Abstract

Human CMV (HCMV) encodes multiple genes that control NK cell activation and cytotoxicity. Some of these HCMV-encoded gene products modulate NK cell activity as ligands expressed at the cell surface that engage inhibitory NK cell receptors, whereas others prevent the infected cell from upregulating ligands that bind to activating NK cell receptors. A major activating NKR is the homodimeric NKG2D receptor, which has eight distinct natural ligands in humans. It was shown that HCMV is able to prevent the surface expression of five of these ligands (MIC A/B and ULBP1, 2, and 6). In this article, we show that the HCMV gene product UL142 can prevent cell surface expression of ULBP3 during infection. We further show that UL142 interacts with ULBP3 and mediates its intracellular retention in a compartment that colocalizes with markers of the cis-Golgi complex. In doing so, UL142 prevents ULBP3 trafficking to the surface and protects transfected cells from NK-mediated cytotoxicity. This is the first description of a viral gene able to mediate downregulation of ULBP3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cytomegalovirus / genetics
  • Cytomegalovirus / metabolism*
  • Cytotoxicity, Immunologic / immunology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Fibroblasts / virology
  • GPI-Linked Proteins
  • Golgi Apparatus / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HeLa Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Space / metabolism
  • Intracellular Space / virology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Microscopy, Fluorescence
  • Protein Transport
  • Recombinant Fusion Proteins / genetics
  • Transfection
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism

Substances

  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • UL142 protein, human herpesvirus 5
  • ULBP3 protein, human
  • Viral Proteins
  • Green Fluorescent Proteins