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Cytoprotective roles of ERK and Akt in endoplasmic reticulum stress triggered by subtilase cytotoxin
Authors:Tian Tian  Zhao Yang  Nakajima Shotaro  Huang Tao  Yao Jian  Paton Adrienne W  Paton James C  Kitamura Masanori
Affiliation:aDepartment of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan;bResearch Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
Abstract:Subtilase cytotoxin (SubAB) is the prototype of a distinct AB5 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.
Keywords:Subtilase cytotoxin   Apoptosis   Extracellular signal-regulated kinase (ERK)   Akt   Endoplasmic reticulum stress   Unfolded protein response (UPR)
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