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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
Statement of
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
CCAAT-Enhancer-Binding Protein-beta
NF-kappa B
Heat-Shock Proteins
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
Appears in Collections:Aurora harvest
Microbiology and Immunology publications

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