Wang Jia C, Lee Jeff Y-J, Christian Sonja, Dang-Lawson May, Pritchard Caitlin, Freeman Spencer A, Gold Michael R
Department of Microbiology & Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
Department of Microbiology & Immunology and the Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3
J Cell Sci. 2017 Mar 15;130(6):1094-1109. doi: 10.1242/jcs.191858. Epub 2017 Feb 6.
B cells that bind antigens displayed on antigen-presenting cells (APCs) form an immune synapse, a polarized cellular structure that optimizes the dual functions of the B cell receptor (BCR), signal transduction and antigen internalization. Immune synapse formation involves polarization of the microtubule-organizing center (MTOC) towards the APC. We now show that BCR-induced MTOC polarization requires the Rap1 GTPase (which has two isoforms, Rap1a and Rap1b), an evolutionarily conserved regulator of cell polarity, as well as cofilin-1, an actin-severing protein that is regulated by Rap1. MTOC reorientation towards the antigen contact site correlated strongly with cofilin-1-dependent actin reorganization and cell spreading. We also show that BCR-induced MTOC polarization requires the dynein motor protein as well as IQGAP1, a scaffolding protein that can link the actin and microtubule cytoskeletons. At the periphery of the immune synapse, IQGAP1 associates closely with F-actin structures and with the microtubule plus-end-binding protein CLIP-170 (also known as CLIP1). Moreover, the accumulation of IQGAP1 at the antigen contact site depends on F-actin reorganization that is controlled by Rap1 and cofilin-1. Thus the Rap1-cofilin-1 pathway coordinates actin and microtubule organization at the immune synapse.
与抗原呈递细胞（APC）上展示的抗原结合的B细胞形成免疫突触，这是一种极化的细胞结构，可优化B细胞受体（BCR）的双重功能，即信号转导和抗原内化。免疫突触的形成涉及微管组织中心（MTOC）向APC的极化。我们现在表明，BCR诱导的MTOC极化需要Rap1 GTP酶（有两种异构体，Rap1a和Rap1b），一种在进化上保守的细胞极性调节因子，以及cofilin-1，一种受Rap1调节的肌动蛋白切割蛋白。MTOC向抗原接触位点的重新定向与cofilin-1依赖的肌动蛋白重组和细胞铺展密切相关。我们还表明，BCR诱导的MTOC极化需要动力蛋白以及IQGAP1，一种可以连接肌动蛋白和微管细胞骨架的支架蛋白。在免疫突触的外围，IQGAP1与F-肌动蛋白结构以及微管正端结合蛋白CLIP-170（也称为CLIP1）紧密结合。此外，IQGAP1在抗原接触位点的积累取决于由Rap1和cofilin-1控制的F-肌动蛋白重组。因此，Rap1-cofilin-1途径在免疫突触处协调肌动蛋白和微管的组织。
