title: Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin.
abstract: Subtilase cytotoxin (SubAB) is the prototype of a distinct AB(5) toxin family produced by Shiga toxigenic Escherichia coli. Recent reports disclosed pro-apoptotic pathways triggered by SubAB, whereas its anti-apoptotic signals have not been elucidated. In the present study, we investigated pro-survival signaling elicited by SubAB, especially focusing on extracellular signal-regulated kinase (ERK) and Akt. We found that SubAB activated ERK and Akt, and inhibition of individual kinases enhanced SubAB-triggered apoptosis. SubAB induced endoplasmic reticulum (ER) stress, and other ER stress inducers mimicked the stimulatory effects of SubAB on ERK and Akt. Attenuation of ER stress reduced SubAB-induced phosphorylation of these kinases, suggesting involvement of the unfolded protein response (UPR). SubAB induced activation of protein kinase-like ER kinase (PERK) and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and phosphorylation of eIF2α by salubrinal caused activation of ERK and Akt, leading to cell survival. Dominant-negative inhibition of PERK enhanced SubAB-induced apoptosis and reduced phosphorylation of ERK and Akt. Furthermore, the anti-apoptotic effect of eIF2α was significantly reversed by inhibition of ERK and Akt. These results suggest cytoprotective roles of ERK and Akt in SubAB-triggered, ER stress-mediated apoptosis.
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: Tian
authors.initials: T
authors.lastname: Tian
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
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: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D029968:Escherichia coli Proteins / Q000633:toxicity*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D013312:Stress, Physiological; D013381:Subtilisins / Q000633:toxicity*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D029968:Escherichia coli Proteins; D015852:Eukaryotic Initiation Factor-2; D048049:Extracellular Signal-Regulated MAP Kinases; D051057:Proto-Oncogene Proteins c-akt; D013381:Subtilisins; D019892:eIF-2 Kinase; C527234:subtilase cytotoxin, E coli