Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing, China.
Natural Products Research Center, Chengdu Institution of Biology, Chinese Academy of Science, Chengdu, China.
J Cell Biol. 2018 Jul 2;217(7):2565-2582. doi: 10.1083/jcb.201711055. Epub 2018 Apr 23.
B lymphocytes use B cell receptors (BCRs) to sense the chemical and physical features of antigens. The activation of isotype-switched IgG-BCR by mechanical force exhibits a distinct sensitivity and threshold in comparison with IgM-BCR. However, molecular mechanisms governing these differences remain to be identified. In this study, we report that the low threshold of IgG-BCR activation by mechanical force is highly dependent on tethering of the cytoplasmic tail of the IgG-BCR heavy chain (IgG-tail) to the plasma membrane. Mechanistically, we show that the positively charged residues in the IgG-tail play a crucial role by highly enriching phosphatidylinositol (4,5)-biphosphate (PI(4,5)P2) into the membrane microdomains of IgG-BCRs. Indeed, manipulating the amounts of PI(4,5)P2 within IgG-BCR membrane microdomains significantly altered the threshold and sensitivity of IgG-BCR activation. Our results reveal a lipid-dependent mechanism for determining the threshold of IgG-BCR activation by mechanical force.
B 细胞利用 B 细胞受体（BCR）来感知抗原的化学和物理特征。与 IgM-BCR 相比，机械力激活同种型转换 IgG-BCR 表现出明显的敏感性和阈值。然而，控制这些差异的分子机制仍有待确定。在这项研究中，我们报告说，机械力激活 IgG-BCR 的低阈值高度依赖于 IgG-BCR 重链胞质尾（IgG-尾）与质膜的连接。在机制上，我们表明 IgG-尾中的正电荷残基通过将磷脂酰肌醇（4,5）-二磷酸（PI（4,5）P2）高度富集到 IgG-BCR 的膜微区中发挥关键作用。实际上，操纵 IgG-BCR 膜微区中的 PI（4,5）P2 量会显著改变 IgG-BCR 激活的阈值和敏感性。我们的结果揭示了一种脂质依赖性机制，用于确定机械力激活 IgG-BCR 的阈值。
