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Article

TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms

Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
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Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(24), 9497; https://doi.org/10.3390/ijms21249497
Received: 13 November 2020 / Revised: 11 December 2020 / Accepted: 12 December 2020 / Published: 14 December 2020
(This article belongs to the Special Issue Kinase Signal Transduction 2020)
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. View Full-Text
Keywords: transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1); reactive oxygen species (ROS); antibacterial agents; macrophages transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1); reactive oxygen species (ROS); antibacterial agents; macrophages
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MDPI and ACS Style

Suzuki, M.; Asai, Y.; Kagi, T.; Noguchi, T.; Yamada, M.; Hirata, Y.; Matsuzawa, A. TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms. Int. J. Mol. Sci. 2020, 21, 9497. https://doi.org/10.3390/ijms21249497

AMA Style

Suzuki M, Asai Y, Kagi T, Noguchi T, Yamada M, Hirata Y, Matsuzawa A. TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms. International Journal of Molecular Sciences. 2020; 21(24):9497. https://doi.org/10.3390/ijms21249497

Chicago/Turabian Style

Suzuki, Midori, Yukino Asai, Tomohiro Kagi, Takuya Noguchi, Mayuka Yamada, Yusuke Hirata, and Atsushi Matsuzawa. 2020. "TAK1 Mediates ROS Generation Triggered by the Specific Cephalosporins through Noncanonical Mechanisms" International Journal of Molecular Sciences 21, no. 24: 9497. https://doi.org/10.3390/ijms21249497

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