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  • Review Article
  • Published:

Shiga toxins — from cell biology to biomedical applications

Nature Reviews Microbiology volume 8, pages 105–116 (2010)Cite this article

Key Points

  • Owing to the oligomeric structure of the Shiga toxin receptor-binding B subunit, these toxins cluster glycosphingolipids to mediate their trafficking into cells.

  • Shiga toxins use poorly explored trafficking pathways to enter cells by clathrin-independent endocytosis and to reach intracellular compartments through the retrograde route.

  • For translocation of the cytotoxic A subunit into the cytosol, Shiga toxins need to be transported to the endoplasmic reticulum, where they use cellular machinery to cross membranes.

  • Shiga toxins kill cells by inhibiting protein biosynthesis. However, they also induce many signalling events that contribute in a major way to the establishment of disease.

  • The expression of globotriaosylceramide, the receptor for Shiga toxins, on dendritic cells and its overexpression by human tumours open possibilities for using the receptor-binding B subunit of Shiga toxins as delivery tools for immunotherapy and targeted tumour therapy.

  • There are several intervention strategies being explored currently, some of which are showing promising results.

Abstract

Shiga toxin-producing Escherichia coli is an emergent pathogen that can induce haemolytic uraemic syndrome. The toxin has received considerable attention not only from microbiologists but also in the field of cell biology, where it has become a powerful tool to study intracellular trafficking. In this Review, we summarize the Shiga toxin family members and their structures, receptors, trafficking pathways and cellular targets. We discuss how Shiga toxin affects cells not only by inhibiting protein biosynthesis but also through the induction of signalling cascades that lead to apoptosis. Finally, we discuss how Shiga toxins might be exploited in cancer therapy and immunotherapy.

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Figure 1: Shiga toxin structures.
Figure 2: Trafficking of Shiga toxins.
Figure 3: The endoplasmic reticulum-associated protein degradation pathway.
Figure 4: Apoptosis pathways that are induced by Shiga toxins.

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Acknowledgements

We thank L. Roberts, J.M. Lord, J. Wiels and C. Lamaze for helpful discussion, and J. Ménétrey for help with figure 1. Work in the laboratory of the authors was supported by CEFIPRA (The Indo-French Centre for the Promotion of Advanced Research; programme n°3803), the Human Frontier Science Program (grant RGP26/2007), the ImmuCan programme of the Pôle de Compétitivité Médicen Paris Région, the Direction Générale de l'Armement programme of Paracell, the Cancerimmunotherapy project in the European Union's Seventh Framework Programme and the Programme indicactif et coopératif (PIC) on Tumour Delivery at the Institut Curie.

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  1. Institut Curie — Centre de Recherche and CNRS UMR144, Traffic, Signalling and Delivery Laboratory, 26 rue d'Ulm, Paris, 75248, Cedex 05, France

    Ludger Johannes & Winfried Römer

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Supplementary information S1 (table)

Trafficking factors that control Shiga toxin transport between early endosomes and the TGN (reviewed in 29). (PDF 158 kb)

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Glossary

Enterohaemorrhagic Escherichia coli

(EHEC). Escherichia coli strains that cause haemorrhagic colitis and haemolytic uraemic syndrome. EHEC constitutes a subset of serotypes called Shiga toxin-producing E. coli (STEC), in which these toxins are virulence factors.

Haemolytic uraemic syndrome

(HUS). A life-threatening complication characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure.

LD50

The median lethal dose of a toxic substance; this is the dose that is required to kill half of the members of a tested population.

Retromer

A heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of cargo molecules from endosomes to the trans-Golgi network.

Coat protein complex I

A large coat protein complex that initiates the vesicle budding process on the cis-Golgi and retrograde transport to the rough endoplasmic reticulum.

Chaperone

A protein that assists in the folding or unfolding of target proteins.

ER-associated degradation

(ERAD). A cellular pathway that targets misfolded proteins in the endoplasmic reticulum for ubiquitylation and subsequent degradation by the proteasome.

Interleukin-8

A chemokine of the C-X-C subfamily that is known to recruit polymorphonuclear cells into areas of infection.

Mitogen-activated protein kinase

(MAPK). One of a family of threonine-directed kinases with important roles in the regulation of diverse cellular functions, including cytokine release. MAPKs are categorized into three main pathways and include the extracellular signal-regulated kinases (ERKs), the JUN amino-terminal kinases (Jnks; also called the stress-activated protein (SAP) kinases) and MAP kinase p38.

Protein kinase Cδ

A member of the protein kinase C family, which contains at least 12 isoforms of serine/threonine kinases that are involved in signal transduction, regulation of gene expression and myeloid differentiation.

GM-CSF

(Granulocyte-macrophage colony-stimulating factor). A protein that is often secreted by macrophages, T cells, endothelial cells and fibroblasts.

Tumour necrosis factor

A cytokine involved in systemic inflammation. Its primary role is the regulation of immune cells.

Topoisomerase I

A group of proteins belonging to the topoisomerase family, which contains enzymes that catalyse ATP-independent breakage of one of the two strands of DNA, passage of the unbroken strand through the break and rejoining of the broken strand. Topoisomerase I enzymes reduce the topological stress in the DNA structure by relaxing the superhelical turns and knotted rings in the DNA helix.

Benzodiazepine

A psychoactive drug, the core chemical structure of which is the fusion of a benzene ring and a diazepine ring. Benzodiazepines have varying sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which make them useful in treating anxiety, insomnia, agitation, seizures, muscle spasms and alcohol withdrawal and as a pre-medication for medical or dental procedures.

Major histocompatibility complex class I

(MHC class I). A molecule found on every nucleated cell of the body. It's function is to display fragments of proteins from within the cell to T cells, so that healthy cells will be left alone and cells with foreign proteins will be attacked by the immune system. Because MHC class I molecules present peptides that are derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.

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Johannes, L., Römer, W. Shiga toxins — from cell biology to biomedical applications. Nat Rev Microbiol 8, 105–116 (2010). https://doi.org/10.1038/nrmicro2279

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