Human Molecular Genetics Advance Access originally published online on August 22, 2005
Human Molecular Genetics 2005 14(19):2881-2892; doi:10.1093/hmg/ddi320
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Fc
RIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling
1Department of Allergy and Rheumatology and 2Department of Human Genetics, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan and 3Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan
* To whom correspondence should be addressed. Tel: +81 338155411 ext. 33175; Fax: +81 338155954; Email: honda-phy{at}h.u-tokyo.ac.jp
Received June 16, 2005; Accepted August 16, 2005
The B cell inhibitory receptor Fc
RIIB plays crucial roles in the maintenance of self-tolerance. We have identified a polymorphism FCGR2B c.695T>C that results in the non-conservative replacement of 232Ile at the transmembrane helix to Thr and demonstrated the association of the polymorphism with susceptibility to systemic lupus erythematosus (SLE) in Asians. In this study, we examined the impact of FCGR2B c.695T>C on the functional properties of FcRIIB by expressing each allele product in a human B cell line ST486 lacking endogenous FcRIIB. FcRIIB 232Thr was found to be significantly less potent than wild-type 232Ile in inhibiting B cell receptor (BCR)-mediated phosphatidylinositol-3,4,5-trisphosphate accumulation, Akt and PLC2 activation and calcium mobilization, and to display decreased levels of tyrosine phosphorylation and SH2-containing 5'-inositolphosphate phosphatase recruitment compared with 232Ile after IgG Fc-mediated coligation with BCR. Notably, a quantitative analysis of the subcellular distribution of FcRIIB using 125I-labeled anti-FcRIIB revealed that FcRIIB 232Thr is less effectively distributed to detergent-insoluble lipid rafts than 232Ile, findings in accordance with the importance of the transmembrane amino acid residues, in particular large hydrophobic amino acids including Ile, in the association of membrane proteins with lipid rafts. Given the crucial roles of lipid rafts in integrating BCR signaling, decreased association of FcRIIB 232Thr could contribute to its impaired inhibitory potential. Collectively, the present findings indicate that the Ile232Thr substitution affects the localization and function of FcRIIB and that the molecular mechanism may link the polymorphism and susceptibility to SLE.
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