Center for Life Sciences, MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing, China.
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.
Immunol Rev. 2019 Sep;291(1):75-90. doi: 10.1111/imr.12775.
To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5-biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2-derived signaling amplification model. Based on these studies, we proposed a "gasoline engine model" in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.
为了有效地针对微环境中的稀有配体启动激活反应，淋巴细胞采用了涉及信号放大的复杂机制。最近，已经报道了一种从磷脂酰肌醇（PI）4,5-二磷酸[PI(4,5)P2]水解和合成开始的信号放大机制，用于持续的 B 细胞激活。抗原和 B 细胞受体（BCR）识别触发了 BCR 微簇内 PI(4,5)P2 密度的迅速减少，导致 BCR 微簇外 PI(4,5)P2 的合成产生正反馈。在单分子水平上，PI(4,5)P2 的扩散速度较慢，允许在 BCR 微簇内外维持 PI(4,5)P2 密度梯度，并持续从 BCR 微簇外向内供应 PI(4,5)P2。在这里，我们回顾了有助于揭示 PI(4,5)P2 衍生信号放大模型的分子机制的研究。基于这些研究，我们提出了一个“汽油发动机模型”，其中微簇内 B 细胞信号的激活类似于汽油发动机燃烧室内部燃烧汽油的工作原理。我们还讨论了表明该模型潜在普遍性的证据和未来前景。
