The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation
The Fas death signaling pathway connecting reactive oxygen species generation and FLICE inhibitory protein down-regulation
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DOI：
10.4049/jimmunol.180.5.3072
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Rojanasakul, Yon
中科院分区：
文献类型：
--
作者：
Wang, Liying;Azad, Neelam;Rojanasakul, Yon
Fas介导的细胞凋亡在正常组织的稳态中起着重要作用，这种死亡途径的破坏有助于许多人类疾病。通过Fas激活诱导细胞凋亡与活性氧（ROS）的产生和FLICE抑制蛋白（FLIP）的下调有关;然而，这两个事件之间的关系及其在Fas介导的细胞凋亡中的作用尚不清楚。我们在此表明，活性氧是必需的FLIP下调和凋亡诱导的Fas配体（FasL）在原代肺上皮细胞。ROS通过泛素化和随后的蛋白酶体降解介导FLIP的下调。通过抗氧化剂或ROS清除酶谷胱甘肽过氧化物酶和超氧化物歧化酶的异位表达抑制ROS有效地抑制了FLIP下调和FasL诱导的凋亡。过氧化氢是负责FLIP下调的主要氧化物质，而超氧化物作为过氧化物的来源和NO的清除剂，其通过S-亚硝基化正向调节FLIP。NADPH氧化酶是FasL诱导的ROS产生的关键来源，显性负性Rac1表达或化学抑制剂抑制NADPH氧化酶可降低细胞对FasL的死亡反应。总之，我们的研究结果表明，FLIP调节的活性氧和氮的相互作用的网络，提供了一个关键的机制，Fas诱导的细胞死亡和相关的凋亡疾病的凋亡调控的新途径。
Fas-mediated apoptosis plays an important role in normal tissue homeostasis, and disruption of this death pathway contributes to many human diseases. Induction of apoptosis via Fas activation has been associated with reactive oxygen species (ROS) generation and down-regulation of FLICE inhibitory protein (FLIP); however, the relationship between these two events and their role in Fas-mediated apoptosis are unclear. We show herein that ROS are required for FLIP down-regulation and apoptosis induction by Fas ligand (FasL) in primary lung epithelial cells. ROS mediate the down-regulation of FLIP by ubiquitination and subsequent degradation by proteasome. Inhibition of ROS by antioxidants or by ectopic expression of ROS-scavenging enzymes glutathione peroxidase and superoxide dismutase effectively inhibited FLIP down-regulation and apoptosis induction by FasL. Hydrogen peroxide is a primary oxidative species responsible for FLIP down-regulation, whereas superoxide serves as a source of peroxide and a scavenger of NO, which positively regulates FLIP via S-nitrosylation. NADPH oxidase is a key source of ROS generation induced by FasL, and its inhibition by dominant-negative Rac1 expression or by chemical inhibitor decreased the cell death response to FasL. Taken together, our results indicate a novel pathway of FLIP regulation by an interactive network of reactive oxygen and nitrogen species that provides a key mechanism of apoptosis regulation in Fas-induced cell death and related apoptosis disorders.