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FCRL3, an Autoimmune Susceptibility Gene, Has Inhibitory Potential on B-Cell Receptor-Mediated Signaling¹

Yuta Kochi,^2* Keiko Myouzen,^* Ryo Yamada,^* Akari Suzuki,^* Tomohiro Kurosaki, Yusuke Nakamura, and Kazuhiko Yamamoto^*¶

^*Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, Tokyo, Japan; Laboratory of Functional Genomics, Human Genome Center, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan; Laboratory of Lymphocyte Differentiation, Research Center for Allergy and Immunology, RIKEN, Yokohama, Japan; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, Tokyo, Japan; and ^¶Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan

A polymorphism that up-regulates the expression of Fc receptor-like 3 (FCRL3) gene has recently been described as predisposing for several human autoimmune diseases. FCRL3 is preferentially expressed on B cells and is unique in displaying both an ITAM and an ITIM in the cytosolic domain, suggesting signaling functions. Herein, we show that FCRL3 potentially inhibits BCR-mediated signaling, using murine FcRIIB/human FCRL3 chimeric protein. Coligation of the chimeric protein with BCR leads to phosphorylation of tyrosine residues in the cytosolic domain. This coligation inhibits cell tyrosine phosphorylation and calcium mobilization in addition to activation-induced cell death mediated by BCR signaling. Mutational analysis showed the tyrosine residues in two potential ITIMs at 662 and 692 offer the main contributions to this inhibition, which is further supported by strong associations of SH-2 domain-containing phosphatases with the following phosphotyrosine motifs: SHIP with the ITIM-like motif at 662; and SHP-1 and -2 with the canonical ITIM at 692. These results, together with previous genetic data, suggest that augmented inhibition of BCR-mediated signaling by FCRL3 with the disease-risk genotype alter the activation threshold and promote tolerance breakdown in B cells.

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 a grant from the Japanese Millennium Project, a grant from CGM, RIKEN, and a grant from Ministry of Health, Labor and Welfare of Japan.

² Address correspondence and reprint requests to Dr. Yuta Kochi, Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, Japan. E-mail address: ykochi{at}src.riken.jp

³ Abbreviations used in this paper: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; FCRL3, Fc receptor-like 3; SHP, Src homology 2 domain-containing phosphatase; HA, hemagglutinin; 7-AAD, 7-amino actinomycin D; CM-WT, chimera wild type; CM-Mt, chimera mutant.