Abstract
The subtilase cytotoxin (SubAB) belongs to the family of AB5 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 AB5 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 AB5 paradigm might be required.
Highlights
Introduction iationsBacterial AB5 toxins are a well-studied protein toxin family, which includes medically relevant members, such as Shiga toxin (Stx), cholera toxin (Ctx), pertussis toxin (Ptx), and the most recently discovered, the subtilase cytotoxin (SubAB)
The latter is produced by certain Stx-producing E. coli (STEC) strains, which are negative for the eae gene that is located in the locus of enterocyte effacement (LEE) [1]
The existence of toxic, single SubA subunits, which were released from the bacteria but have not found a SubB-pentamer for holotoxin assembly, might broaden and enhance the pathogenic potential of subtilase-producing E. coli strains
Summary
Introduction iationsBacterial AB5 toxins are a well-studied protein toxin family, which includes medically relevant members, such as Shiga toxin (Stx), cholera toxin (Ctx), pertussis toxin (Ptx), and the most recently discovered, the subtilase cytotoxin (SubAB). Key Contribution: This mini review summarizes research of recent years that the A-subunit SubA of the subtilase cytotoxin, an AB5 –type protein toxin of Shiga toxin-producing E. coli strains (STEC), is taken up into cells and exhibits cytotoxic effects by proteolysis of the ER chaperone BiP/GRP78 in the absence of its transport subunit SubB, challenging the paradigm of AB-type protein toxins. Recent publications show that the A subunit of the subtilase cytotoxin (SubA) can cause cell death in the absence of its corresponding B subunit (SubB) [8,9].
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