Combs Jeffrey, Kim Soo Jin, Tan Sarah, Ligon Lee A, Holzbaur Erika L F, Kuhn Jeffrey, Poenie Martin
Department of Molecular Cell and Developmental Biology, University of Texas, 1 University Station, MC C0930, Austin, TX 78712, USA.
Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14883-8. doi: 10.1073/pnas.0600914103. Epub 2006 Sep 21.
Binding of T cells to antigen-presenting cells leads to the formation of the immunological synapse, translocation of the microtubule-organizing center (MTOC) to the synapse, and focused secretion of effector molecules. Here, we show that upon activation of Jurkat cells microtubules project from the MTOC to a ring of the scaffolding protein ADAP, localized at the synapse. Loss of ADAP, but not lymphocyte function-associated antigen 1, leads to a severe defect in MTOC polarization at the immunological synapse. The microtubule motor protein cytoplasmic dynein clusters into a ring at the synapse, colocalizing with the ADAP ring. ADAP coprecipitates with dynein from activated Jurkat cells, and loss of ADAP prevents MTOC translocation and the specific recruitment of dynein to the synapse. These results suggest a mechanism that links signaling through the T cell receptor to translocation of the MTOC, in which the minus end-directed motor cytoplasmic dynein, localized at the synapse through an interaction with ADAP, reels in the MTOC, allowing for directed secretion along the polarized microtubule cytoskeleton.
T细胞与抗原呈递细胞的结合会导致免疫突触的形成、微管组织中心(MTOC)向突触的转位以及效应分子的集中分泌。在此,我们表明,在Jurkat细胞激活后,微管从MTOC伸出至位于突触处的支架蛋白ADAP环。ADAP的缺失而非淋巴细胞功能相关抗原1的缺失,会导致免疫突触处MTOC极化出现严重缺陷。微管运动蛋白胞质动力蛋白在突触处聚集成环,与ADAP环共定位。ADAP与激活的Jurkat细胞中的动力蛋白共沉淀,ADAP的缺失会阻止MTOC转位以及动力蛋白向突触的特异性募集。这些结果提示了一种将通过T细胞受体的信号传导与MTOC转位联系起来的机制,其中通过与ADAP相互作用定位于突触的负端定向运动蛋白胞质动力蛋白,将MTOC卷入,从而允许沿极化的微管细胞骨架进行定向分泌。