title: Subtilase cytotoxin activates MAP kinases through PERK and IRE1 branches of the unfolded protein response.
abstract: Recent reports suggested involvement of mitogen-activated protein (MAP) kinases in the pathogenesis of Shiga toxin-induced hemolytic uremic syndrome (HUS). In the present study, we investigated a role for subtilase cytotoxin (SubAB), a possible trigger for HUS, in the regulation of MAP kinases. Treatment of cells with SubAB caused phosphorylation of c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase (ERK), and p38 MAP kinase. It was associated with activation of activator protein 1 (AP-1) and induction of AP-1-dependent transcription. SubAB induced the unfolded protein response (UPR) and consequently caused MAP kinase activation. SubAB led to induction of three major branches of the UPR, and the protein kinase-like endoplasmic reticulum kinase and inositol-requiring ER-to-nucleus signal kinase 1 pathways were responsible for the activation of MAP kinases. These results elucidated the potential of SubAB to trigger MAP kinase pathways via the UPR, which may contribute to the pathogenesis of Shiga toxin-induced HUS.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Saito
authors.forename: Shuhei
authors.initials: S
authors.lastname: Takahashi
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: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D013381:Subtilisins / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics; D014162:Transfection; D056811:Unfolded Protein Response / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D013381:Subtilisins; D018808:Transcription Factor AP-1; D019892:eIF-2 Kinase; C486557:Ern2 protein, rat; C527234:subtilase cytotoxin, E coli