Rho family proteins modulate rapid apoptosis induced by cytotoxic T lymphocytes and Fas
Rho family proteins modulate rapid apoptosis induced by cytotoxic T lymphocytes and Fas
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DOI：
10.1074/jbc.275.13.9725
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发表时间：
2000-03-31
影响因子：
4.8
通讯作者：
Hahn, KM
中科院分区：
文献类型：
--
作者：
Subauste, MC;Von Herrath, M;Hahn, KM
Rho蛋白在细胞凋亡中的作用知之甚少，这些细胞凋亡是由细胞毒性T淋巴细胞（CTL）和Fas的颗粒酶等刺激物引起的。在这里，我们证明了所有三个Rho家族成员都参与了CTL和Fas诱导的杀伤。每个Rho家族成员的显性阴性突变体和所有家族成员的抑制剂艰难梭菌毒素B强烈抑制细胞对CTL和Fas诱导的凋亡的易感性。Fas诱导的caspase-3激活被C，difilicile毒素抑制，每个GT3的激活突变体增加对凋亡的敏感性，并且Cdc 42的激活在Fas刺激5 min内增加。相反，在CTL和Fas杀伤所需的时间内，显性阴性或活化突变体或单独艰难梭菌毒素均不产生细胞凋亡。使用latrunculin A抑制肌动蛋白聚合降低了组成型活性GT3突变体刺激细胞凋亡的能力，并阻断了Fas诱导的caspase-3活化。此外，Rac增强细胞凋亡的能力被报告的点突变阻断Rac诱导肌动蛋白聚合而降低，Rho家族蛋白可能通过其对肌动蛋白细胞骨架的影响来调节细胞凋亡。
Little is known about the role of Rho proteins in apoptosis produced by stimuli evolved specifically to produce apoptosis, such as granzymes from cytotoxic T lymphocytes (CTLs) and Fas, Here we demonstrate that all three Rho family members are involved in CTL- and Fas-induced killing. Dominant-negative mutants of each Rho family member and Clostridium difficile toxin B, an inhibitor of all family members, strongly inhibited the susceptibility of cells to CTL- and Fas-induced apoptosis. Fas-induced caspase-3 activation was inhibited by C, diflicile toxin, Activated mutants of each GTPase increased susceptibility to apoptosis, and activation of Cdc42 increased within 5 min of Fas stimulation. In contrast, during the time required for CTL and Fas killing, no apoptosis was produced by dominant-negative or activated mutants or by C, difficile toxin alone. Inhibition of actin polymerization using latrunculin A reduced the ability of constitutively active GTPase mutants to stimulate apoptosis and blocked Fas-induced activation of caspase-3. Furthermore, the ability of Rac to enhance apoptosis was decreased by point mutations reported to block Rac induction of actin polymerization, Rho family proteins may regulate apoptosis through their effects on the actin cytoskeleton.