Special Issue "Shiga Toxin"
Deadline for manuscript submissions: closed (30 April 2011)
Prof. Dr. Clifford A. Lingwood (Website)
Division of Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
Fax: +1 416 8135993
Gastrointestinal Shiga toxin (Stx) producing E. coli (STEC) infections are the major cause of the hemolytic uremic syndrome (HUS). This nephropathy remains a significant pediatric health hazard world-wide, for which there is still no specific therapy. The lack of appropriate animal models has hampered therapeutic progress. Other than age (most HUS occurs in the very young), risk factors for HUS following STEC infection have yet to de identified. Cattle provide an animal STEC reservoir and fecal contaminated foodstuffs remain the major infection source. Stx is an AB5 subunit toxin. The pentamer of (small) B subunits binding to its receptor glycosphingolipid(GSL), globotriaosyl ceramide(Gb3) in glomerular endothelial cell membranes, initiates A subunit-mediated cell death leading to HUS, but induction of inflammatory pathways is also key. Gb3 is heterogenous in its lipid structure and membrane organization, such that different Gb3 formats are differentially recognized by Stx family members, particularly Stx2, which is more frequently associated with clinical disease.
Stx binding to Gb3 also provides a biological probe of membrane GSL organization and intracellular vesicular retrograde transport. Internalization of the Stx-Gb3 complex by clathrin dependent and independent means can result in transit via endosomes, trans Golgi network and Golgi, to the endoplasmic reticulum, necessary for subunit separation and A subunit cytosolic translocation. The A subunit is an RNA glycanase which depurinates cytosolic 28S ribosomal subunits to inhibit protein synthesis. Signalling cascades which initiate apoptosis are also found downstream of Stx cell membrane Gb3 binding. The association of Gb3 with cholesterol can result in Stx binding to cell membrane lipid microdomains or rafts which is central to both signal transduction and cytotoxicity.
Stx also has antineoplastic activity due to Gb3 upregulation, and the B subunit can be used for tumour targeting.
Prof. Dr. Clifford A. Lingwood
- hemolytic uremic syndrome
- retrograde transport
- endothelial cells