Ministry of Education (MOE) 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 100084, China.
National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Sci Immunol. 2017 Nov 17;2(17). doi: 10.1126/sciimmunol.aan0787.
Lymphocytes have evolved sophisticated signaling amplification mechanisms to efficiently activate downstream signaling after detection of rare ligands in their microenvironment. B cell receptor microscopic clusters (BCR microclusters) are assembled on the plasma membrane and recruit signaling molecules for the initiation of lymphocyte signaling after antigen binding. We identified a signaling amplification loop derived from phosphatidylinositol 4,5-biphosphate (PIP) for the sustained B cell activation. Upon antigen recognition, PIP was depleted by phospholipase C-γ2 (PLC-γ2) within the BCR microclusters and was regenerated by phosphatidic acid-dependent type I phosphatidylinositol 4-phosphate 5-kinase outside the BCR microclusters. The hydrolysis of PIP inside the BCR microclusters induced a positive feedback mechanism for its synthesis outside the BCR microclusters. The falling gradient of PIP across the boundary of BCR microclusters was important for the efficient formation of BCR microclusters. Our results identified a PIP-derived amplification loop that fuels the sustained initiation of B cell activation.
淋巴细胞已经进化出复杂的信号放大机制，以便在其微环境中检测到稀有配体后，有效地激活下游信号。B 细胞受体微小簇（BCR 微小簇）在质膜上组装，并在抗原结合后招募信号分子，以启动淋巴细胞信号。我们发现了一个源自磷脂酰肌醇 4,5-二磷酸（PIP）的信号放大环，用于持续的 B 细胞激活。在抗原识别后，BCR 微小簇内的磷脂酶 C-γ2（PLC-γ2）消耗 PIP，而 BCR 微小簇外的依赖于磷酸脂酸的 I 型磷脂酰肌醇 4-磷酸 5-激酶则再生 PIP。BCR 微小簇内 PIP 的水解诱导了其在 BCR 微小簇外合成的正反馈机制。BCR 微小簇边界处 PIP 的下降梯度对于 BCR 微小簇的有效形成很重要。我们的结果确定了一个由 PIP 衍生的放大环，为持续启动 B 细胞激活提供动力。
