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Association of FcRIIa (CD32a) with Lipid Rafts Regulates Ligand Binding Activity¹

Stylianos Bournazos^*,, Simon P. Hart, Luke H. Chamberlain, Martin J. Glennie^¶ and Ian Dransfield^2,*

^* University of Edinburgh/Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, Edinburgh, U.K.; Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, U.K.; Division of Cardiovascular and Respiratory Studies, Hull York Medical School/University of Hull, Cottingham, U.K.; Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, U.K.; and ^¶ Tenovus Research Laboratory, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, U.K.

Binding of Igs to myeloid cells via FcR is a key event in the control of innate and acquired immunity. FcRIIa (CD32a) is a receptor for multivalent IgG expressed predominantly by myeloid cells, and its association with microdomains rich in cholesterol and sphingolipids, termed as lipid rafts, has been reported to be essential for efficient signaling. However, for many myeloid cell types, ligand binding to CD32a is suppressed by as yet undefined mechanisms. In this study, we have examined the role of CD32a-lipid raft interactions in the regulation of IgG binding to CD32a. Disruption of lipid raft structure following depletion or sequestration of membrane cholesterol greatly inhibited CD32a-mediated IgG binding. Furthermore, specific CD32a mutants, which show reduced association with lipid rafts (A224S and C241A), displayed decreased levels of IgG binding compared with wild-type CD32a. In contrast, constitutively lipid raft-associated CD32a (GPI-anchored CD32a) exhibited increased capacity for IgG binding compared with the full-length transmembrane CD32a. Our findings clearly suggest a major role for lipid rafts in the regulation of IgG binding and, more specifically, that suppression of CD32a-mediated IgG binding in myeloid cells is achieved by receptor exclusion from lipid raft membrane microdomains.

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 supported by grants from the British Heart Foundation (FS/05/119/19568; to S.B.) and the Medical Research Council (to S.P.H.).

² Address correspondence and reprint requests to Prof. Ian Dransfield, University of Edinburgh/Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, U.K. E-mail address: i.dransfield{at}ed.ac.uk

³ Abbreviations used in this paper: ROI, reactive oxygen intermediate; BxB, biotin anti-biotin immune complex; CD, -cyclodextrin; CHO, Chinese hamster ovary; DRM, detergent-resistant membrane; hHAIgG, human heat-aggregated IgG; HNE, human neutrophil elastase; MβCD, methyl-β-cyclodextrin; shRNA, short hairpin RNA; TfR, transferrin receptor; WT, wild type.