MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing 100084, China.
Biochemistry and Structural Biology Lab, Department of Biology, Syed Babar Ali School of Science and Engineering, Lahore University of Management of Sciences (LUMS) Lahore, Pakistan.
Sci Adv. 2019 Jul 17;5(7):eaaw0315. doi: 10.1126/sciadv.aaw0315. eCollection 2019 Jul.
B cell activation is regulated by the stimulatory or inhibitory co-receptors of B cell receptors (BCRs). Here, we investigated the signaling mechanism of Fc receptor-like 1 (FcRL1), a newly identified BCR co-receptor. FcRL1 was passively recruited into B cell immunological synapses upon BCR engagement in the absence of FcRL1 cross-linking, suggesting that FcRL1 may intrinsically regulate B cell activation and function. BCR cross-linking alone led to the phosphorylation of the intracellular YENV motif of FcRL1 to provide a docking site for c-Abl, an SH2 domain-containing kinase. The FcRL1 and c-Abl signaling module, in turn, potently augmented B cell activation and proliferation. FcRL1-deficient mice exhibited markedly impaired formation of extrafollicular plasmablasts and germinal centers, along with decreased antibody production upon antigen stimulation. These findings reveal a critical BCR signal-enhancing function of FcRL1 through its intrinsic recruitment to B cell immunological synapses and subsequent recruitment of c-Abl upon BCR cross-linking.
B 细胞的激活受 B 细胞受体（BCR）的刺激或抑制共受体调节。在这里，我们研究了新鉴定的 BCR 共受体 Fc 受体样蛋白 1（FcRL1）的信号转导机制。在没有 FcRL1 交联的情况下，FcRL1 可被动募集到 B 细胞免疫突触中，这表明 FcRL1 可能内在调节 B 细胞的激活和功能。BCR 交联本身导致 FcRL1 的细胞内 YENV 基序磷酸化，为含有 SH2 结构域的激酶 c-Abl 提供了一个对接位点。反过来，FcRL1 和 c-Abl 信号模块强烈增强了 B 细胞的激活和增殖。FcRL1 缺陷小鼠在抗原刺激时表现出滤泡外浆母细胞和生发中心形成明显受损，抗体产生减少。这些发现揭示了 FcRL1 通过其内在募集到 B 细胞免疫突触，并在 BCR 交联后募集 c-Abl，从而发挥关键的 BCR 信号增强功能。
