title: Selective abrogation of BiP/GRP78 blunts activation of NF-κB through the ATF6 branch of the UPR: involvement of C/EBPβ and mTOR-dependent dephosphorylation of Akt.
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.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Saito
authors.forename: Hironori
authors.initials: H
authors.lastname: Kato
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.forename: Adrienne W
authors.initials: AW
authors.lastname: Paton
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Masanori
authors.initials: M
authors.lastname: Kitamura
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D058767:Protein Unfolding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C497113:Atf6 protein, rat; D022782:CCAAT-Enhancer-Binding Protein-beta; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases