Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London, WC2A 3LY, UK.
Immunity. 2011 Jun 24;34(6):905-18. doi: 10.1016/j.immuni.2011.06.001.
The B cell receptor (BCR) mediates B cell antigen gathering and acquisition for presentation to T cells. Although the amount of antigen presentation to T cells determines the extent of B cell activation, the molecular mechanisms underlying antigen gathering remain unexplored. Here, through a combination of high-resolution imaging, genetics and quantitative mass spectrometry, we demonstrate that adaptors Grb2 and Dok-3, and ubiquitin ligase Cbl in signaling BCR microclusters mediate association with the microtubule motor dynein. Furthermore, we visualize the localization and movement of these microclusters on the underlying microtubule network. Importantly, disruption of this network or diminished dynein recruitment in Grb2-, Dok-3-, or Cbl-deficient B cells, does not influence microcluster formation or actin-dependent spreading, but abrogates directed movement of microclusters and antigen accumulation. Thus we identify a surprising but pivotal role for dynein and the microtubule network alongside Grb2, Dok-3, and Cbl in antigen gathering during B cell activation.
B 细胞受体 (BCR) 介导 B 细胞抗原聚集和摄取，以便呈递给 T 细胞。尽管抗原呈递给 T 细胞的量决定了 B 细胞激活的程度，但抗原聚集的分子机制仍未被探索。在这里，我们通过高分辨率成像、遗传学和定量质谱分析相结合的方法，证明了信号转导 BCR 微簇中的衔接蛋白 Grb2 和 Dok-3 以及泛素连接酶 Cbl 与微管动力蛋白 dynein 发生关联。此外，我们还观察到这些微簇在基底微管网络上的定位和运动。重要的是，破坏该网络或在 Grb2、Dok-3 或 Cbl 缺陷 B 细胞中减少 dynein 的募集，不会影响微簇的形成或肌动蛋白依赖性扩展，但会破坏微簇的定向运动和抗原积累。因此，我们发现了一个令人惊讶但至关重要的作用，即在 B 细胞激活过程中，dynein 和微管网络与 Grb2、Dok-3 和 Cbl 一起，在抗原聚集中发挥作用。
