TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms.
TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms.
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DOI：
10.3390/ijms21249497
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发表时间：
2020-12-14
影响因子：
5.6
通讯作者：
Matsuzawa A
中科院分区：
文献类型：
--
作者：
Suzuki M;Asai Y;Kagi T;Noguchi T;Yamada M;Hirata Y;Matsuzawa A
已知多种抗菌剂刺激哺乳动物细胞中活性氧（ROS）的产生。然而，其机制在很大程度上是未知的。在这项研究中，我们意外地发现，转化生长因子-β（TGF-β）激活的激酶1（TAK 1）参与了由头孢噻肟（CTX）启动的线粒体ROS（mtROS）的产生，头孢噻肟是一种特异性抗菌头孢菌素，可以触发氧化应激诱导的细胞死亡。TAK 1缺陷型巨噬细胞被发现对H2 O2刺激的氧化应激诱导的细胞死亡敏感。然而，奇怪的是，TAK 1缺陷型巨噬细胞对CTX刺激的氧化应激诱导的细胞死亡表现出很强的抵抗力。显微镜分析显示，CTX诱导的ROS产生被TAK 1的敲除或抑制所覆盖，这表明TAK 1的激酶活性是CTX诱导的ROS产生所必需的。有趣的是，药物阻断TAK 1下游通路，如核因子-κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）通路，并不影响CTX诱导的ROS产生。此外，我们观察到，CTX促进TAK 1易位到线粒体。总之，这些观察结果表明，线粒体TAK 1介导的CTX诱导的mtROS的产生通过非经典机制。因此，我们的数据表明，一种新的和非典型的功能TAK 1介导的特定头孢菌素引发的线粒体ROS的产生。
It is known that a wide variety of antibacterial agents stimulate generation of reactive oxygen species (ROS) in mammalian cells. However, its mechanisms are largely unknown. In this study, we unexpectedly found that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is involved in the generation of mitochondrial ROS (mtROS) initiated by cefotaxime (CTX), one of specific antibacterial cephalosporins that can trigger oxidative stress-induced cell death. TAK1-deficient macrophages were found to be sensitive to oxidative stress-induced cell death stimulated by H2O2. Curiously, however, TAK1-deficient macrophages exhibited strong resistance to oxidative stress-induced cell death stimulated by CTX. Microscopic analysis revealed that CTX-induced ROS generation was overridden by knockout or inhibition of TAK1, suggesting that the kinase activity of TAK1 is required for CTX-induced ROS generation. Interestingly, pharmacological blockade of the TAK1 downstream pathways, such as nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, did not affect the CTX-induced ROS generation. In addition, we observed that CTX promotes translocation of TAK1 to mitochondria. Together, these observations suggest that mitochondrial TAK1 mediates the CTX-induced mtROS generation through noncanonical mechanisms. Thus, our data demonstrate a novel and atypical function of TAK1 that mediates mtROS generation triggered by the specific cephalosporins.
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影响因子：
5.6
作者：
Noguchi T;Tsuchida M;Kogue Y;Spadini C;Hirata Y;Matsuzawa A
通讯作者：
Matsuzawa A
影响因子：
11.2
作者：
Omori E;Matsumoto K;Zhu S;Smart RC;Ninomiya-Tsuji J
通讯作者：
Ninomiya-Tsuji J
影响因子：
5.6
作者：
Hirata Y;Takahashi M;Morishita T;Noguchi T;Matsuzawa A
通讯作者：
Matsuzawa A
影响因子：
64.5
作者：
Kohanski, Michael A.;Dwyer, Daniel J.;Collins, James J.
通讯作者：
Collins, James J.
影响因子：
4.3
作者：
Chen, Zhiyu;Shen, Xiaolu;Lai, Jiang
通讯作者：
Lai, Jiang