Nolz Jeffrey C, Medeiros Ricardo B, Mitchell Jason S, Zhu Peimin, Freedman Bruce D, Shimizu Yoji, Billadeau Daniel D
Department of Immunology and Division of Oncology Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Mol Cell Biol. 2007 Sep;27(17):5986-6000. doi: 10.1128/MCB.00136-07. Epub 2007 Jun 25.
T-cell-receptor (TCR)-mediated integrin activation is required for T-cell-antigen-presenting cell conjugation and adhesion to extracellular matrix components. While it has been demonstrated that the actin cytoskeleton and its regulators play an essential role in this process, no mechanism has been established which directly links TCR-induced actin polymerization to the activation of integrins. Here, we demonstrate that TCR stimulation results in WAVE2-ARP2/3-dependent F-actin nucleation and the formation of a complex containing WAVE2, ARP2/3, vinculin, and talin. The verprolin-connecting-acidic (VCA) domain of WAVE2 mediates the formation of the ARP2/3-vinculin-talin signaling complex and talin recruitment to the immunological synapse (IS). Interestingly, although vinculin is not required for F-actin or integrin accumulation at the IS, it is required for the recruitment of talin. In addition, RNA interference of either WAVE2 or vinculin inhibits activation-dependent induction of high-affinity integrin binding to VCAM-1. Overall, these findings demonstrate a mechanism in which signals from the TCR produce WAVE2-ARP2/3-mediated de novo actin polymerization, leading to integrin clustering and high-affinity binding through the recruitment of vinculin and talin.
T细胞受体(TCR)介导的整合素激活是T细胞与抗原呈递细胞结合以及黏附于细胞外基质成分所必需的。虽然已经证明肌动蛋白细胞骨架及其调节因子在此过程中起重要作用,但尚未建立直接将TCR诱导的肌动蛋白聚合与整合素激活联系起来的机制。在此,我们证明TCR刺激导致依赖WAVE2-ARP2/3的F-肌动蛋白成核,并形成包含WAVE2、ARP2/3、纽蛋白和踝蛋白的复合物。WAVE2的维普罗林连接酸性(VCA)结构域介导ARP2/3-纽蛋白-踝蛋白信号复合物的形成以及踝蛋白募集至免疫突触(IS)。有趣的是,虽然纽蛋白并非IS处F-肌动蛋白或整合素积累所必需,但它是踝蛋白募集所必需的。此外,WAVE2或纽蛋白的RNA干扰抑制了激活依赖性高亲和力整合素与血管细胞黏附分子-1(VCAM-1)结合的诱导。总体而言,这些发现证明了一种机制,即来自TCR的信号产生WAVE2-ARP2/3介导的肌动蛋白从头聚合,通过募集纽蛋白和踝蛋白导致整合素聚集和高亲和力结合。