Novel Aspects of the SubA Subunit of the Subtilase Cytotoxin

The subtilase cytotoxin (SubAB) belongs to the family of AB(5) toxins and is produced together with Shiga toxin (Stx) by certain Stx-producing E. coli strains (STEC). For most AB-type toxins, it is assumed that cytotoxic effects can only be induced by a complete holotoxin complex consisting of SubA and SubB. However, it has been shown for SubAB that the enzymatically active subunit SubA, without its transport and binding domain SubB, induces cell death in different eukaryotic cell lines. Interestingly, the molecular structure of SubA resembles that of the SubAB complex. SubA alone is capable of binding to cells and then being taken up autonomously. Once inside the host cell, SubA is transported, similar to the SubAB holotoxin, via a retrograde transport into the endoplasmatic reticulum (ER). In the ER, it exhibits its enzymatic activity by cleaving the chaperone BiP/GRP78 and thereby triggering cell death. Therefore, the existence of toxic single SubA subunits that have not found a B-pentamer for holotoxin assembly might improve the pathogenic potential of subtilase-producing strains. Moreover, from a pharmacological aspect, SubA might be an interesting molecule for the targeted transport of therapeutic molecules into the ER, in order to investigate and specifically modulate processes in the context of ER stress-associated diseases. Since recent studies on bacterial AB(5) toxins contributed mainly to the understanding of the biology of AB-type holotoxins, this mini-review specifically focus on that recently observed single A-effect of the subtilase cytotoxin and addresses whether a fundamental shift of the traditional AB(5) paradigm might be required.

Automated summary

The subtilase cytotoxin (SubAB) is a member of the AB(5) toxin family produced by certain Shiga toxin-producing E. coli strains. The enzymatically active subunit SubA of SubAB can induce cell death independently, offering potential pathogenic implications for the bacteria. This unique feature also suggests the possible use of SubA for targeted transport of therapeutic molecules into the endoplasmic reticulum to study and modulate processes related to ER stress-associated diseases.