Subtilase cytotoxin activates PERK, IRE1 and ATF6 endoplasmic reticulum stress-signalling pathways.
Subtilase cytotoxin (SubAB) is the prototype of a new family of AB(5) 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 eIF2alpha, 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.
Wolfson
Jennifer J
JJ
Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Boston, MA 02111, USA.
May
Kerrie L
KL
Thorpe
Cheleste M
CM
Jandhyala
Dakshina M
DM
Paton
James C
JC
Paton
Adrienne W
AW
D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D054323:Shiga-Toxigenic Escherichia coli / Q000378:metabolism*; D015398:Signal Transduction; D013381:Subtilisins / Q000378:metabolism*; D014709:Vero Cells; D019892:eIF-2 Kinase / Q000378:metabolism*
D051702:Activating Transcription Factor 6; D029968:Escherichia coli Proteins; D017346:Protein Serine-Threonine Kinases; D013381:Subtilisins; D019892:eIF-2 Kinase; C527234:subtilase cytotoxin, E coli