Escherichia coli subtilase cytotoxin induces apoptosis regulated by host Bcl-2 family proteins Bax/Bak.
Subtilase cytotoxin (SubAB) was first isolated from a Shiga toxigenic Escherichia coli (STEC) strain that was responsible for an outbreak of hemolytic-uremic syndrome and is the prototype of a new family of AB(5) cytotoxins. SubAB is a subtilase-like serine protease, and upon uptake by host cells, it is trafficked to the endoplasmic reticulum (ER), where it cleaves the essential ER chaperone BiP (GRP78) with high specificity. Previous work has shown that BiP cleavage by SubAB initiates ER stress-signaling pathways in host cells that eventuate in cell death associated with DNA fragmentation, a hallmark of apoptosis. The present study has investigated the role of the Bcl-2 protein family, which has been shown to regulate ER stress-induced apoptosis in other model systems. Examination of the cytotoxicity of SubAB for wild-type and bax(-/-)/bak(-/-) mouse embryonic fibroblasts and comparison of apoptotic markers in these cells revealed that SubAB cytotoxicity can be predominantly attributed to the activation of apoptotic pathways activated by Bax/Bak. The results of the present study further our understanding of the molecular mechanism whereby SubAB kills eukaryotic cells and contributes to STEC pathogenesis, in addition to consolidating the roles of Bcl-2 family members in the regulation of ER stress-induced apoptosis.
May
Kerrie L
KL
Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
Paton
James C
JC
Paton
Adrienne W
AW
D000818:Animals; D017209:Apoptosis; D002522:Chlorocebus aethiops; D053938:DNA Fragmentation; D004721:Endoplasmic Reticulum / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins / Q000633:toxicity*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D051379:Mice; D054323:Shiga-Toxigenic Escherichia coli / Q000472:pathogenicity*; D013381:Subtilisins / Q000633:toxicity*; D014709:Vero Cells; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D000091342:Endoplasmic Reticulum Chaperone BiP; D029968:Escherichia coli Proteins; C000717248:Hspa5 protein, mouse; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D013381:Subtilisins; C527234:subtilase cytotoxin, E coli