title: FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling.
abstract: The B cell inhibitory receptor FcgammaRIIB 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 FcgammaRIIB by expressing each allele product in a human B cell line ST486 lacking endogenous FcgammaRIIB. FcgammaRIIB 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 PLCgamma2 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 FcgammaRIIB using 125I-labeled anti-FcgammaRIIB revealed that FcgammaRIIB 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 FcgammaRIIB 232Thr could contribute to its impaired inhibitory potential. Collectively, the present findings indicate that the Ile232Thr substitution affects the localization and function of FcgammaRIIB and that the molecular mechanism may link the polymorphism and susceptibility to SLE.
authors.affiliation: Department of Allergy and Rheumatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kono
authors.forename: Chieko
authors.initials: C
authors.lastname: Kyogoku
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tsuchiya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Zen-Ichiro
authors.initials: Z
authors.lastname: Honda
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D021962:Membrane Microdomains / Q000276:immunology*; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011110:Polymorphism, Genetic; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017452:Receptors, IgG / Q000032:analysis / Q000235:genetics*; D015398:Signal Transduction; D013912:Threonine / Q000235:genetics
chemical_list: D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D018129:Phosphatidylinositol Phosphates; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; C060974:phosphatidylinositol 3,4,5-triphosphate; D007532:Isoleucine; D013912:Threonine