Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways
Article first published online: 21 APR 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd
Volume 10, Issue 9, pages 1775–1786, September 2008
How to Cite
Wolfson, J. J., May, K. L., Thorpe, C. M., Jandhyala, D. M., Paton, J. C. and Paton, A. W. (2008), Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways. Cellular Microbiology, 10: 1775–1786. doi: 10.1111/j.1462-5822.2008.01164.x
- Issue published online: 5 AUG 2008
- Article first published online: 21 APR 2008
- Received 12 November, 2007; revised 11 April, 2008; accepted 14 April, 2008.
Subtilase cytotoxin (SubAB) is the prototype of a new family of AB5 cytotoxins produced by Shiga toxigenic Escherichia coli. Its cytotoxic activity is due to its capacity to enter cells and specifically cleave the essential endoplasmic reticulum (ER) chaperone BiP (GRP78). In the present study, we have examined its capacity to trigger the three ER stress-signalling pathways in Vero cells. Activation of PKR-like ER kinase was demonstrated by phosphorylation of eIF2α, which occurred within 30 min of toxin treatment, and correlated with inhibition of global protein synthesis. Activation of inositol-requiring enzyme 1 was demonstrated by splicing of X-box-binding protein 1 mRNA, while activating transcription factor 6 activation was demonstrated by depletion of the 90 kDa uncleaved form, and appearance of the 50 kDa cleaved form. The rapidity with which ER stress-signalling responses are triggered by exposure of cells to SubAB is consistent with the hypothesis that cleavage by the toxin causes BiP to dissociate from the signalling molecules.