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Department of Pathology, University of Cambridge, United Kingdom
Recognition of MHC class I-related chain (MIC) molecules on the surface of target cells by the activating receptor NKG2D leads to their lysis by immune effector cells. Up-regulation of NKG2D ligands is broadly related to stress, although the detailed molecular mechanisms that control the presence of these molecules at the plasma membrane are unclear. To investigate the posttranslational mechanisms that control surface expression of the human NKG2D ligand MICB, we studied the subcellular localization and trafficking of this molecule. We found that in several cellular systems, the expression of MICB molecules on the cell surface is accompanied by an intracellular accumulation of the molecule in the trans-Golgi network and late endosome-related compartments. Surprisingly, MICB has a much shorter half-life at the plasma membrane than MHC molecules and this depends on both recycling to internal compartments and shedding to the extracellular medium. Internalization of MICB depends partially on clathrin, but importantly, the lipid environment of the membrane also plays a crucial role in this process. We suggest that the brief residence of MICB at the plasma membrane modulates, at least in part, the function of this molecule in the immune system.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by a Leukemia Research Fund Project Grant (to H.T.R. and M.V.G.). M.V.G. is a recipient of a New Investigator Grant from the Medical Research Council and an International Joint Project from the Royal Society. S.A. was supported by fellowships from the Fundación Caja Madrid and Ibercaja. P.B. was supported in part by The Newton Trust.
2 S.A.-G. and P.B. contributed equally to the work presented.
3 Address correspondence and reprint requests to Dr. Mar Valés-Gómez, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom
4 Abbreviations used in this paper: MICA/B, MHC class I chain-related gene A/B; MESNA, 2,mercaptoethane sulfonic acid; DRM, detergent-resistant membrane; HCMV, human CMV; TGN, trans-Golgi network; CI-M6PR, cation-independent mannose-6-phosphate receptor; ER, endoplasmic reticulum; EEA1, early endosome A1; LAMP-1, lysosome-activated membrane protein 1; CHX, cycloheximide; BFA, brefeldin A; CHL, chloroquine; MβCD, methyl-β-cyclodextrin.
5 The online version of this article contains supplemental material.
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