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Human Molecular Genetics Advance Access published online on August 22, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi320
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 16, 2005
Revised August 16, 2005
Accepted August 16, 2005

Article

Fc{gamma}RIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling

Hajime Kono 1, Chieko Kyogoku 2, Takeshi Suzuki 1, Naoyuki Tsuchiya 2, Hiroaki Honda 3, Kazuhiko Yamamoto 1, Katsushi Tokunaga 2, and Zen-ichiro Honda 1*

1 Department of Allergy and Rheumatology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
2 Department of Human Genetics, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
3 Department 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.
Zen-ichiro Honda, E-mail: honda-phy{at}h.u-tokyo.ac.jp


  Abstract

The B cell inhibitory receptor Fc{gamma}RIIB plays crucial roles in the maintenance of self-tolerance. We have identified a polymorphism FCGR2B c.695T > C that results in the nonconservative 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 the present study we examined the impact of FCGR2B c.695T > C on the functional properties of Fc{gamma}RIIB by expressing each allele product in a human B cell line ST486 lacking endogenous Fc{gamma}RIIB. Fc{gamma}RIIB 232Thr was found to be significantly less potent than wild type 232Ile in inhibiting B cell receptor (BCR)-mediated PIP3 accumulation, Akt and PLC{gamma}2 activation and calcium mobilization, and to display decreased levels of tyrosine phosphorylation and SHIP recruitment compared with 232Ile after IgG Fc-mediated coligation with BCR. Notably, a quantitative analysis of the subcellular distribution of Fc{gamma}RIIB using 125I-labeled anti-Fc{gamma}RIIB revealed that Fc{gamma}RIIB 232Thr 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 Fc{gamma}RIIB 232Thr could contribute to its impaired inhibitory potential. Collectively, the present findings indicate that the Ile232Thr substitution affects the localization and function of Fc{gamma}RIIB, and that the molecular mechanism may link the polymorphism and susceptibility to SLE.


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