Intracellular sequestration of the NKG2D ligand ULBP3 by human cytomegalovirus.
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.
Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
Neil J
NJ
Bennett
Omodele
O
Ashiru
Fiona J E
FJ
Morgan
Yin
Y
Pang
Georgina
G
Okecha
Rob A
RA
Eagle
John
J
Trowsdale
J G Patrick
JG
Sissons
Mark R
MR
Wills
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D058851:GPI-Linked Proteins; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism / Q000821:virology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C512704:UL142 protein, human herpesvirus 5; C423229:ULBP3 protein, human; D014764:Viral Proteins; D049452:Green Fluorescent Proteins