Shiga toxin

Ribbon diagram of Shiga toxin (Stx) from S. dysenteriae. From PDB: 1R4Q​.

Shiga toxins are a family of related toxins with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the genome of lambdoid prophages.[1] The toxins are named after Kiyoshi Shiga, who first described the bacterial origin of dysentery caused by Shigella dysenteriae.[2] The most common sources for Shiga toxin are the bacteria S. dysenteriae and the shigatoxigenic serotypes of Escherichia coli (STEC), which includes serotypes O157:H7, and O104:H4.[3][4]

Nomenclature

Microbiologists use many terms to describe Shiga toxin and differentiate more than one unique form. Many of these terms are used interchangeably.

  1. Shiga toxin type 1 and type 2 (Stx-1 and 2) are the Shiga toxins produced by some E. coli strains. Stx-1 is identical to Stx of Shigella spp. or differs by only one amino acid.[5] Stx-2 shares 56% sequence identity with Stx-1.
  2. Cytotoxins – an archaic denotation for Stx – is used in a broad sense.
  3. Verocytotoxins/verotoxins – a seldom-used term for Stx – is from the hypersensitivity of Vero cells to Stx.
  4. The term Shiga-like toxins is another antiquated term which arose prior to the understanding that shiga and shiga-like toxins were identical.

Mechanism

Shiga toxins act to inhibit protein synthesis within target cells by a mechanism similar to that of ricin.[6] After entering a cell via a macropinosome,[7] the protein cleaves a specific adenine nucleobase from the 28S RNA of the 60S subunit of the ribosome, thereby halting protein synthesis.[8]

The bacterial Shiga toxin can be used for targeted therapy of gastric cancer, because this tumor entity expresses the receptor of the Shiga toxin. For this purpose an unspecific chemotherapeutical is conjungated to the B-subunit to make it specific. In this way only the tumor cells, but not healthy cells, are destroyed during therapy.[9]

Structure

The toxin has two subunits—designated A (mol. wt. 32000 D) and B (mol. wt. 7700 D)—and is one of the AB5 toxins. The B subunit is a pentamer that binds to specific glycolipids on the host cell, specifically globotriaosylceramide (Gb3). Following this, the A subunit is internalised and cleaved into two parts. The A1 component then binds to the ribosome, disrupting protein synthesis. Stx-2 has been found to be about 400 times more toxic (as quantified by LD50 in mice) than Stx-1.

Gb3 is, for unknown reasons, present in greater amounts in renal epithelial tissues, to which the renal toxicity of Shiga toxin may be attributed. Gb3 is also found in central nervous system neurons and endothelium, which may lead to neurotoxicity.[10] Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.[11]

The toxin requires highly specific receptors on the cells' surface to attach and enter the cell; species such as cattle, swine, and deer which do not carry these receptors may harbor toxigenic bacteria without any ill effect, shedding them in their feces, from where they may be spread to humans.[12]

See also

References

  1. ↑ Friedman D; Court D (2001). "Bacteriophage lambda: alive and well and still doing its thing". Current Opinion in Microbiology. 4 (2): 201–7. doi:10.1016/S1369-5274(00)00189-2. PMID 11282477.
  2. ↑ Trofa, Andrew F.; Ueno-Olsen, Hannah; Oiwa, Ruiko; Yoshikawa, Masanosuke (1999-11-01). "Dr. Kiyoshi Shiga: Discoverer of the Dysentery Bacillus". Clinical Infectious Diseases. 29 (5): 1303–1306. doi:10.1086/313437. ISSN 1058-4838.
  3. ↑ Beutin L (2006). "Emerging enterohaemorrhagic Escherichia coli, causes and effects of the rise of a human pathogen". Journal of veterinary medicine. B, Infectious diseases and veterinary public health. 53 (7): 299–305. doi:10.1111/j.1439-0450.2006.00968.x. PMID 16930272.
  4. ↑ Spears; et al. (2006). "A comparison of Enteropathogenic and enterohaemorragic E.coli pathogenesis". FEMS Microbiology Letters. 255 (2): 187–202. doi:10.1111/j.1574-6968.2006.00119.x. PMID 16448495.
  5. ↑ Kaper JB, O'Brien AD (2014). "Overview and Historical Perspectives". Microbiology Spectrum. 2 (6). doi:10.1128/microbiolspec.EHEC-0028-2014. PMC 4290666. PMID 25590020.
  6. ↑ Sandvig K; van Deurs B (2000). "Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives". The EMBO Journal. 19 (22): 5943–50. doi:10.1093/emboj/19.22.5943. PMC 305844. PMID 11080141.
  7. ↑ Lukyanenko, V.; Malyukova, I.; Hubbard, A.; Delannoy, M.; Boedeker, E.; Zhu, C.; Cebotaru, L.; Kovbasnjuk, O. (2011). "Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells". AJP: Cell Physiology. 301 (5): C1140–C1149. doi:10.1152/ajpcell.00036.2011. PMC 3213915. PMID 21832249.
  8. ↑ Sandvig K; Bergan J; Dyve A; Skotland T; Torgersen M.L. (2010). "Endocytosis and retrograde transport of Shiga toxin". Reviews of infectious diseases. 56 Suppl 7 (7): 1181–1185. doi:10.1016/j.toxicon.2009.11.021. PMID 2047652.
  9. ↑ Gastric adenocarcinomas express the glycosphingolipid Gb3/CD77: Targeting of gastric cancer cells with Shiga toxin B-subunit
  10. ↑ Obata F; Tohyama K; Bonev AD; Kolling GL; Keepers TR; Gross LK; Nelson MT; Sato S; Obrig TG (2008). "Shiga Toxin 2 Affects the Central Nervous System through Receptor Globotriaosylceramide Localized to Neurons". The Journal of Infectious Diseases. 198 (9): 1398–1406. doi:10.1086/591911. PMC 2684825. PMID 18754742.
  11. ↑ Tironi-Farinati C; Loidl CF; Boccoli J; Parma Y; Fernandez-Miyakawa ME; Goldstein J. (2010). "Intracerebroventricular Shiga toxin 2 increases the expression of its receptor globotriaosylceramide and causes dendritic abnormalities". Journal of neuroimmunology. 222 (1–2): 48–61. doi:10.1016/j.jneuroim.2010.03.001. PMID 20347160.
  12. ↑ Asakura H; Makino S; Kobori H; Watarai M; Shirahata T; Ikeda T; Takeshi K (2001). "Phylogenetic diversity and similarity of active sites of Shiga toxin (stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals". Epidemiology and Infection. 127 (1): 27–36. doi:10.1017/S0950268801005635. PMC 2869726. PMID 11561972.
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