Haga Christopher L, Ehrhardt Götz R A, Boohaker Rebecca J, Davis Randall S, Cooper Max D
Division of Developmental and Clinical Immunology, Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9770-5. doi: 10.1073/pnas.0703354104. Epub 2007 May 23.
The Fc receptor-like protein 5 (FCRL5) on B cells has both an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence and two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor FcgammaRIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SH2-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Igalpha/Igbeta heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.
B细胞上的Fc受体样蛋白5（FCRL5）在其胞质区域既有一个基于免疫受体酪氨酸的激活基序（ITAM）样序列，又有两个保守的基于免疫受体酪氨酸的抑制基序（ITIM）。为了评估其信号传导潜力，我们在缺乏内源性Fc受体的B细胞系中表达了由FCRL5的胞质区域与IgG Fc受体FcγRIIB的细胞外和跨膜区域组成的嵌合分子构建体。该融合蛋白与B细胞受体（BCR）的共结合抑制了BCR介导的钙动员、细胞内酪氨酸磷酸化和Erk激酶激活。我们的突变分析表明，虽然连接后抑制基序和激活基序中的酪氨酸均被磷酸化，但只有ITIM中的酪氨酸影响BCR介导的信号传导。这种FCRL5抑制作用是通过含SH2结构域的蛋白酪氨酸磷酸酶SHP-1的双重ITIM募集介导的，SHP-1进而使BCR Igα/Igβ异二聚体中基于ITAM的酪氨酸去磷酸化。FCRL5对BCR信号传导的抑制作用在原代B细胞中同样得到证实。尽管其配体目前尚不清楚，但我们得出结论，FCRL5具有作为人类成熟B细胞上抑制性共受体的功能潜力。
