Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Oncogene. 2010 Mar 4;29(9):1374-83. doi: 10.1038/onc.2009.417. Epub 2009 Nov 23.
Ezrin links cortical actin filaments with the cell membrane, and has a critical role in many membrane-initiated events. Fas is directly associated with ezrin, but conflicting results have been reported for the involvement of ezrin in Fas-induced cell death. In this study we show that ezrin was associated with Fas in T cells before stimulation and was released shortly after Fas ligand (FasL) engagement. The knockdown of ezrin moderately increased Fas-triggered or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-triggered cell death in normal T lymphocytes and in H9 cells, but had no effect on death receptor-induced apoptosis in type II cells, such as Jurkat and CEM. Expression of a dominant-negative form of ezrin also led to an increased Fas-induced apoptosis in H9 cells. Ezrin deficiency did not affect the internalization of Fas after Fas ligation. Instead, an enhanced formation of death-inducing signaling complex (DISC) was observed in H9 cells with ezrin knockdown, leading to accelerated caspase-8 activation. Together, our results suggest that ezrin has a negative role in the recruitment of Fas into signaling complexes in type I T cells. Loss of ezrin likely removes the constraint imposed by ezrin and facilitates the assembly of death receptor complex in T cells.
埃兹蛋白将皮质肌动蛋白丝与细胞膜连接起来，在许多由膜引发的事件中起着关键作用。Fas 直接与埃兹蛋白相关联，但埃兹蛋白在 Fas 诱导的细胞死亡中的作用存在相互矛盾的结果。在这项研究中，我们发现在刺激前 T 细胞中 Fas 与埃兹蛋白相关联，并且在 Fas 配体（FasL）结合后不久就被释放。埃兹蛋白的敲低在正常 T 淋巴细胞和 H9 细胞中适度增加了 Fas 触发或肿瘤坏死因子相关凋亡诱导配体（TRAIL）触发的细胞死亡，但对 II 型细胞（如 Jurkat 和 CEM）中的死亡受体诱导的凋亡没有影响。表达显性失活形式的埃兹蛋白也导致 H9 细胞中 Fas 诱导的凋亡增加。埃兹蛋白缺失不影响 Fas 结合后 Fas 的内化。相反，在埃兹蛋白敲低的 H9 细胞中观察到诱导死亡信号复合物（DISC）的形成增强，导致 caspase-8 的激活加速。总之，我们的结果表明，埃兹蛋白在 I 型 T 细胞中将 Fas 募集到信号复合物中起着负性作用。埃兹蛋白的缺失可能会消除埃兹蛋白施加的限制，并促进 T 细胞中死亡受体复合物的组装。
