Actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration
Actin cytoskeleton regulates calcium dynamics and NFAT nuclear duration
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DOI：
10.1128/mcb.24.4.1628-1639.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Gajewski, TF
中科院分区：
文献类型：
--
作者：
Rivas, FV;O'Keefe, JP;Gajewski, TF
抗原提呈细胞对t细胞的激活伴随着肌动蛋白聚合、t细胞受体（TCR）封顶和免疫突触的形成。然而，对于t细胞功能是否需要肌动蛋白依赖事件，人们知之甚少。在此，我们为肌动蛋白细胞骨架在tcr诱导的细胞因子产生中意想不到的负调节作用提供了证据。肌动蛋白聚合的破坏导致细胞内钙升高时间延长，以响应抗cd3、thapsigargin或肉豆蔻酸酯佛波酯加离子霉素，导致持续的NFAT（活化T细胞的核因子）核持续时间。这些事件是显性的，因为肌动蛋白阻断的净效应是增强白细胞介素2启动子活性。刺激后质膜Ca2+- atp酶的表面表达增加，被细胞松弛素D抑制，表明肌动蛋白聚合有助于钙的输出。我们的研究结果表明肌动蛋白细胞骨架在调节Ca2+-NFAT信号传导持续时间中的新作用，并表明肌动蛋白动力学调节受体聚集下游t细胞活化的特征。
T-cell activation by antigen-presenting cells is accompanied by actin polymerization, T-cell receptor (TCR) capping, and formation of the immunological synapse. However, whether actin-dependent events are required for T-cell function is poorly understood. Herein, we provide evidence for an unexpected negative regulatory role of the actin cytoskeleton on TCR-induced cytokine production. Disruption of actin polymerization resulted in prolonged intracellular calcium elevation in response to anti-CD3, thapsigargin, or phorbol myristate acetate plus ionomycin, leading to persistent NFAT (nuclear factor of activated T cells) nuclear duration. These events were dominant, as the net effect of actin blockade was augmented interleukin 2 promoter activity. Increased surface expression of the plasma membrane Ca2+-ATPase was observed upon stimulation, which was inhibited by cytochalasin D, suggesting that actin polymerization contributes to calcium export. Our results imply a novel role for the actin cytoskeleton in modulating the duration of Ca2+-NFAT signaling and indicate that actin dynamics regulate features of T-cell activation downstream of receptor clustering.