Abstract
The cellular entry of the bacterial Shiga toxin and the related verotoxins has been scrutinized in quite some detail. This is due to their importance as a threat to human health. At the same time, the study of Shiga toxin has allowed the discovery of novel molecular mechanisms that also apply to the intracellular trafficking of endogenous proteins at the plasma membrane and in the endosomal system. In this review, the individual steps that lead to Shiga toxin uptake into cells will first be presented from a purely mechanistic perspective. Membrane-biological concepts will be highlighted that are often still poorly explored, such as fluctuation force-driven clustering, clathrin-independent membrane curvature generation, friction-driven scission, and retrograde sorting on early endosomes. It will then be explored whether and how these also apply to other pathogens, pathogenic factors, and cellular proteins. The molecular nature of Shiga toxin as a carbohydrate-binding protein and that of its cellular receptor as a glycosylated raft lipid will be an underlying theme in this discussion. It will thereby be illustrated how the study of Shiga toxin has led to the proposal of the GlycoLipid-Lectin (GL-Lect) hypothesis on the generation of endocytic pits in processes of clathrin-independent endocytosis.
Highlights
Shiga toxin is a pathogenic protein that is produced by Shigella dysenteriae, while enterohemorrhagic strains of Escherichia coli secrete Shiga-like toxins, which are termed verotoxins [1]
The verotoxins of E. coli strain O157:H7 are responsible for pathological manifestations that can lead to hemolytic-uremic syndrome (HUS), the leading cause for pediatric renal failure in the world [2]
Because of the positioning of 10 of the Gb3 binding pockets at the rim of STxB molecules in a location slightly above the normal plane of the membrane, the latter must bend up to reach these sites, thereby generating an increment of negative, inward-oriented curvature. This binding site geometry is preserved for the receptor-binding parts of cholera toxin and simian virus 40 (SV40) (Figure 3c), for which it was shown previously that they have curvature-active properties, endowing them with the capacity to drive tubular membrane invaginations through interaction with their GSL receptor molecules [25], as observed for Shiga toxin [9]
Summary
Shiga toxin is a pathogenic protein that is produced by Shigella dysenteriae, while enterohemorrhagic strains of Escherichia coli secrete Shiga-like toxins, which are termed verotoxins [1]. The verotoxins of E. coli strain O157:H7 are responsible for pathological manifestations that can lead to hemolytic-uremic syndrome (HUS), the leading cause for pediatric renal failure in the world [2]. These toxins are a threat to adults as it became apparent in 2011, when an outbreak with E. coli strain O104:H4 in Germany and neighboring countries claimed dozens of adult victims, and thousands of adult patients who were hospitalized with severe symptoms. They need the non-covalent interaction with receptor-binding homopentameric B-subunits.
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