The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 29 March 2004 doi:10.1084/jem.20032194
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 1005-1010
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Brief Definitive Report

 Cell Surface Organization of Stress-inducible Proteins ULBP and MICA That Stimulate Human NK Cells and T Cells via NKG2D

Konstantina Eleme1, Sabrina B. Taner1, Björn Önfelt1, Lucy M. Collinson1, Fiona E. McCann1, N. Jan Chalupny3, David Cosman3, Colin Hopkins1, Anthony I. Magee2, and Daniel M. Davis1

1 Department of Biological Sciences and 2 Department of Biomedical Sciences, Imperial College, London SW7 2AZ, UK
3 Amgen, Seattle, WA 98101

Address correspondence to Daniel M. Davis, Dept. of Biological Sciences, Sir Alexander Fleming Building, Imperial College, London SW7 2AZ, UK. Phone: 44-207-594-5420; Fax: 44-207-594-3044; email: d.davis{at}imperial.ac.uk

Cell surface proteins major histocompatibility complex (MHC) class I–related chain A (MICA) and UL16-binding proteins (ULBP) 1, 2, and 3 are up-regulated upon infection or tumor transformation and can activate human natural killer (NK) cells. Patches of cross-linked raft resident ganglioside GM1 colocalized with ULBP1, 2, 3, or MICA, but not CD45. Thus, ULBPs and MICA are expressed in lipid rafts at the cell surface. Western blotting revealed that glycosylphosphatidylinositol (GPI)-anchored ULBP3 but not transmembrane MICA, MHC class I protein, or transferrin receptor, accumulated in detergent-resistant membranes containing GM1. Thus, MICA may have a weaker association with lipid rafts than ULBP3, yet both proteins accumulate at an activating human NK cell immune synapse. Target cell lipid rafts marked by green fluorescent protein–tagged GPI also accumulate with ULBP3 at some synapses. Electron microscopy reveals constitutive clusters of ULBP at the cell surface. Regarding a specific molecular basis for the organization of these proteins, ULBP1, 2, and 3 and MICA are lipid modified. ULBP1, 2, and 3 are GPI anchored, and we demonstrate here that MICA is S-acylated. Finally, expression of a truncated form of MICA that lacks the putative site for S-acylation and the cytoplasmic tail can be expressed at the cell surface, but is unable to activate NK cells.

Key Words: immunological synapse • natural killer cell • fluorescence imaging • lipid rafts • intercellular communication

K. Eleme, S.B. Taner, and B. Önfelt contributed equally to this work.


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