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https://hdl.handle.net/2440/66182
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Type: | Journal article |
Title: | Selective abrogation of BiP/GRP78 blunts activation of NF-κΒ through the ATF6 branch of the UPR: involvement of C/EBPβ and mTOR-dependent dephosphorylation of Akt |
Other Titles: | Selective abrogation of BiP/GRP78 blunts activation of NF-kappaBeta through the ATF6 branch of the UPR: involvement of C/EBPbeta and mTOR-dependent dephosphorylation of Akt |
Author: | Nakajima, S. Hiramatsu, N. Hayakawa, K. Saito, Y. Kato, H. Huang, T. Yao, J. Paton, A. Paton, J. Kitamura, M. |
Citation: | Molecular and Cellular Biology, 2011; 31(8):1710-1718 |
Publisher: | Amer Soc Microbiology |
Issue Date: | 2011 |
ISSN: | 0270-7306 1098-5549 |
Statement of Responsibility: | Shotaro Nakajima, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Yukinori Saito, Hironori Kato, Tao Huang, Jian Yao, Adrienne W. Paton, James C. Paton, and Masanori Kitamura |
Abstract: | Subtilase cytotoxin (SubAB) that selectively cleaves BiP/GRP78 triggers the unfolded protein response (UPR) and protects mice from endotoxic lethality and collagen arthritis. We found that pretreatment of cells with SubAB suppressed tumor necrosis alpha (TNF-α)-induced activation of NF-κB and NF-κB-dependent chemokine expression. To elucidate underlying mechanisms, the involvement of C/EBP and Akt, putative regulators of NF-κB, was investigated. Among members of the C/EBP family, SubAB preferentially induced C/EBPβ. Overexpression of C/EBPβ suppressed TNF-α-induced NF-κB activation, and knockdown of C/EBPβ attenuated the suppressive effect of SubAB on NF-κB. We identified that the ATF6 branch of the UPR plays a crucial role in the induction of C/EBPβ. In addition to this effect, SubAB depressed basal and TNF-α-induced phosphorylation of Akt via the UPR. It was mediated by the induction of ATF6 and consequent activation of mTOR that dephosphorylated Akt. Inhibition of Akt attenuated activation of NF-κB by TNF-α, suggesting that the mTOR-Akt pathway is another target for SubAB-initiated, UPR-mediated NF-κB suppression. These results elucidated that SubAB blunts activation of NF-κB through ATF6-dependent mechanisms, i.e., preferential induction of C/EBPβ and mTOR-dependent dephosphorylation of Akt. |
Keywords: | Cells, Cultured Animals Mice Rats CCAAT-Enhancer-Binding Protein-beta NF-kappa B Heat-Shock Proteins Phosphorylation Proto-Oncogene Proteins c-akt Activating Transcription Factor 6 TOR Serine-Threonine Kinases Protein Unfolding |
Rights: | Copyright © 2011, American Society for Microbiology. All Rights Reserved. |
DOI: | 10.1128/MCB.00939-10 |
Published version: | http://dx.doi.org/10.1128/mcb.00939-10 |
Appears in Collections: | Aurora harvest Microbiology and Immunology publications |
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