Abstract
Subtilase cytotoxin (SubAB) is the prototype of a new AB5 toxin family produced by a subset of Shiga toxigenic Escherichia coli (STEC) strains. Its A subunit is a subtilase-like serine protease and cytotoxicity for eukaryotic cells is due to a highly specific, single-site cleavage of BiP/GRP78, an essential Hsp70 family chaperone located in the endoplasmic reticulum (ER). This cleavage triggers a severe and unresolved ER stress response, ultimately triggering apoptosis. The B subunit has specificity for glycans terminating in the sialic acid N-glycolylneuraminic acid. Although its actual role in human disease pathogenesis is yet to be established, SubAB is lethal for mice and induces pathological features overlapping those seen in the haemolytic uraemic syndrome, a life-threatening complication of STEC infection. The toxin is also proving to be a useful tool for probing the role of BiP and ER stress in a variety of cellular functions.
Highlights
AB5 toxins are key virulence factors for several notorious bacterial pathogens, which collectively cause massive global morbidity and mortality, amongst children in developing countries.There are three well-characterized AB5 toxin families, namely the Shiga toxins (Stx) produced byShiga toxigenic Escherichia coli (STEC) and Shigella dysenteriae, cholera toxin (Ctx) and the closely related labile enterotoxins (LT) produced by Vibrio cholerae and enterotoxigenic E. coli, respectively, Toxins 2010, 2 and pertussis toxin (Ptx) produced by Bordetella pertussis
SubAB was discovered in a strain of STEC belonging to serotype O113:H21 that caused an outbreak of haemolytic uraemic syndrome (HUS) in South Australia [3]
At least for PERK and inositol-requiring enzyme 1 (IRE1), the rapidity with which endoplasmic reticulum (ER) stress signaling 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 signaling molecules, without the need for accumulation of unfolded proteins in the ER lumen
Summary
AB5 toxins are key virulence factors for several notorious bacterial pathogens, which collectively cause massive global morbidity and mortality, amongst children in developing countries. There are three well-characterized AB5 toxin families, namely the Shiga toxins (Stx) produced by. A subunits capable of disrupting critical host cell functions, non-covalently linked to pentameric B subunits that bind to specific glycan receptors on target eukaryotic cells triggering toxin uptake [1]. The A subunits of Stx toxins are RNA-N-glycosidases which cleave a specific adenine base in 28S rRNA, thereby inhibiting eukaryotic protein synthesis in the same manner as the plant toxin ricin. The. A subunits of Ctx/LT and Ptx are ADP-ribosylases which modify distinct host G proteins, resulting in alteration of intracellular cAMP levels and disregulation of ion transport mechanisms [1]. Subtilase cytotoxin (SubAB) is the prototype of a fourth AB5 toxin family, with a mechanism of action that differs from that of the other three families [2]. We summarise current knowledge regarding the molecular and cellular biology, role in disease pathogenesis, and potential cell biological applications of this new toxin
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