Journal Article

Subtilase Cytotoxin Activates MAP Kinases through PERK and IRE1 Branches of the Unfolded Protein Response

Yang Zhao, Tian Tian, Tao Huang, Shotaro Nakajima, Yukinori Saito, Shuhei Takahashi, Jian Yao, Adrienne W. Paton, James C. Paton and Masanori Kitamura

in Toxicological Sciences

Volume 120, issue 1, pages 79-86
Published in print March 2011 | ISSN: 1096-6080
Published online December 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq368
Subtilase Cytotoxin Activates MAP Kinases through PERK and IRE1 Branches of the Unfolded Protein Response

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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 NH2-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.

Keywords: subtilase cytotoxin; c-Jun NH2-terminal kinase; extracellular signal-regulated kinase; p38 mitogen-activated protein kinase; unfolded protein response

Journal Article.  3978 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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