TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death
TNF-induced activation of the Nox1 NADPH oxidase and its role in the induction of necrotic cell death
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DOI：
10.1016/j.molcel.2007.04.021
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发表时间：
2007-06-08
期刊：
影响因子：
16
通讯作者：
Liu, Zheng-Gang
中科院分区：
文献类型：
--
作者：
Kim, You-Sun;Morgan, Michael J.;Liu, Zheng-Gang
肿瘤坏死因子（tumor necrosis factor，TNF）是一种重要的免疫和炎症细胞因子，可诱导多种细胞反应，包括凋亡和坏死。TNF信号通过激活NADPH氧化酶Nox 2/gp 91使吞噬细胞和血管细胞中产生超氧化物。在这里，我们表明，TNF也激活小鼠成纤维细胞的Nox 1 NADPH氧化酶时，细胞发生坏死。TNF处理诱导形成含有TRADD、RIP 1、Nox 1和小GTTR Rac 1的信号复合物。TNF处理的RIP 1缺陷的成纤维细胞不能形成这样的复合物，表明RIP 1是Nox 1招聘必不可少的。此外，用TRADD或Rac 1的显性负突变体预防TNF诱导的超氧化物生成，以及使用siRNA敲低Nox 1，抑制坏死。因此，我们的研究表明，通过与TNF信号组分形成复合物来激活Nox 1在TNF诱导的坏死细胞死亡中起关键作用。
Tumor necrosis factor (TNF) is an important cytokine in immunity and inflammation and induces many cellular responses, including apoptosis and necrosis. TNF signaling enables the generation of superoxide in phagocytic and vascular cells through the activation of the NADPH oxidase Nox2/gp91. Here we show that TNF also activates the Nox1 NADPH oxidase in mouse fibroblasts when cells undergo necrosis. TNF treatment induces the formation of a signaling complex containing TRADD, RIP1, Nox1, and the small GTPase Rac1. TNF-treated RIP1-deficient fibroblasts fail to form such a complex, indicating that RIP1 is essential for Nox1 recruitment. Moreover, the prevention of TNF-induced superoxide generation with dominant-negative mutants of TRADD or Rac1, as well as knockdown of Nox1 using siRNA, inhibits necrosis. Thus our study suggests that activation of Nox1 through forming a complex with TNF signaling components plays a key role in TNF-induced necrotic cell death.