Current studentsExisting staffContact us
 

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

Simple item page
dc.contributor.authorNakajima, S.
dc.contributor.authorHiramatsu, N.
dc.contributor.authorHayakawa, K.
dc.contributor.authorSaito, Y.
dc.contributor.authorKato, H.
dc.contributor.authorHuang, T.
dc.contributor.authorYao, J.
dc.contributor.authorPaton, A.
dc.contributor.authorPaton, J.
dc.contributor.authorKitamura, M.
dc.date.issued2011
dc.description.abstractSubtilase 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.
dc.description.statementofresponsibilityShotaro Nakajima, Nobuhiko Hiramatsu, Kunihiro Hayakawa, Yukinori Saito, Hironori Kato, Tao Huang, Jian Yao, Adrienne W. Paton, James C. Paton, and Masanori Kitamura
dc.identifier.citationMolecular and Cellular Biology, 2011; 31(8):1710-1718
dc.identifier.doi10.1128/MCB.00939-10
dc.identifier.issn0270-7306
dc.identifier.issn1098-5549
dc.identifier.orcidPaton, J. [0000-0001-9807-5278]
dc.identifier.urihttp://hdl.handle.net/2440/66182
dc.language.isoen
dc.publisherAmer Soc Microbiology
dc.rightsCopyright © 2011, American Society for Microbiology. All Rights Reserved.
dc.source.urihttps://doi.org/10.1128/mcb.00939-10
dc.subjectCells, Cultured
dc.subjectAnimals
dc.subjectMice
dc.subjectRats
dc.subjectCCAAT-Enhancer-Binding Protein-beta
dc.subjectNF-kappa B
dc.subjectHeat-Shock Proteins
dc.subjectPhosphorylation
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectActivating Transcription Factor 6
dc.subjectTOR Serine-Threonine Kinases
dc.subjectProtein Unfolding
dc.subjectEndoplasmic Reticulum Chaperone BiP
dc.titleSelective 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
dc.title.alternativeSelective 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
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Microbiology and Immunology publications