Editing Shiga toxin (section)

==Structure and mechanism==
[[File:1R4P Structure.png|thumb|300x300px|SLT2 from [[Escherichia coli O157:H7|''Escherichia coli'' O157:H7]]. A-subunit is shown above (viridian), with B-subunit [[pentamer]] below (multicolored). From {{PDB|1R4P}}.]]

=== Mechanism ===
The B subunits of the toxin bind to a component of the [[cell membrane]] known as glycolipid [[globotriaosylceramide]] (Gb3). Binding of the subunit B to Gb3 causes induction of narrow tubular membrane invaginations, which drives formation of inward membrane tubules for toxin-receptor complex<ref name="pmid21297888">{{cite journal|vauthors=Obrig TG|title=''Escherichia coli'' Shiga Toxin Mechanisms of Action in Renal Disease|journal=Toxins|volume=2|issue=12|pages=2769–2794|doi=10.3390/toxins2122769|doi-access=free|year=2010|pmid=21297888|pmc=3032420}}</ref> uptake into the cell. These tubules are essential for uptake into the host cell.<ref name="pmid18046403">{{cite journal | vauthors = Römer W, Berland L, Chambon V, Gaus K, Windschiegl B, Tenza D, Aly MR, Fraisier V, Florent JC, Perrais D, Lamaze C, Raposo G, Steinem C, Sens P, Bassereau P, Johannes L | title = Shiga toxin induces tubular membrane invaginations for its uptake into cells | journal = Nature | volume = 450 | issue = 7170 | pages = 670–5 | date = November 2007 | pmid = 18046403 | doi = 10.1038/nature05996 | bibcode = 2007Natur.450..670R | s2cid = 4410673}}</ref>
The Shiga toxin (a non-pore forming toxin) is transferred to the cytosol via Golgi network and [[endoplasmic reticulum]] (ER). From the Golgi toxin is trafficked to the ER.  It is then processed through cleavage by a [[furin]]-like protease to separate the A1 subunit.  Some toxin-receptor complexes reportedly bypass these steps and are transported to the nucleus rather than the cytosol, with unknown effects.<ref name="pmid21297888"/>

Shiga toxins act to inhibit [[protein synthesis]] within target cells by a mechanism similar to that of the infamous plant toxin [[ricin]].<ref name=Sandvig_2000>{{cite journal | vauthors = Sandvig K, van Deurs B | title = Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives | journal = The EMBO Journal | volume = 19 | issue = 22 | pages = 5943–50 | date = November 2000 | pmid = 11080141 | pmc = 305844 | doi = 10.1093/emboj/19.22.5943 }}</ref><ref name=Mercatelli_2020>{{cite journal | vauthors = Mercatelli D, Bortolotti M, Giorgi FM | title = Transcriptional network inference and master regulator analysis of the response to ribosome-inactivating proteins in leukemia cells | journal = Toxicology | volume = 441 | date = August 2020 | page = 152531 | doi = 10.1016/j.tox.2020.152531 | pmid = 32593706 | bibcode = 2020Toxgy.44152531M | s2cid = 220255474 }}</ref> After entering a cell via a [[macropinosome]],<ref>{{cite journal | vauthors = Lukyanenko V, Malyukova I, Hubbard A, Delannoy M, Boedeker E, Zhu C, Cebotaru L, Kovbasnjuk O | title = Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells | journal = American Journal of Physiology. Cell Physiology | volume = 301 | issue = 5 | pages = C1140-9 | date = November 2011 | pmid = 21832249 | pmc = 3213915 | doi = 10.1152/ajpcell.00036.2011 }}</ref> the payload (A subunit) cleaves a specific adenine [[nucleobase]] from the [[28S RNA]] of the [[Eukaryotic large ribosomal subunit (60S)|60S subunit of the ribosome]], thereby halting protein synthesis.<ref name=Sandvig_2010>{{cite journal | vauthors = Donohue-Rolfe A, Acheson DW, Keusch GT | title = Shiga toxin: purification, structure, and function | journal = Reviews of Infectious Diseases | volume = 13 Suppl 4 | issue = 7 | pages = S293-7 | year = 2010 | pmid = 2047652 | doi = 10.1016/j.toxicon.2009.11.021 }}</ref> As they mainly act on the lining of the [[blood vessels]], the vascular endothelium, a breakdown of the lining and hemorrhage eventually occurs.{{clarify|date=December 2015}} {{citation needed span|text=The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminated [[food]] or [[water]].|date=October 2024}}

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 conjugated to the B-subunit to make it specific. In this way only the tumor cells, but not healthy cells, are destroyed during therapy.<ref>Gastric adenocarcinomas express the glycosphingolipid Gb3/CD77: Targeting of gastric cancer cells with Shiga toxin B-subunit</ref>

=== Structure ===
The toxin has two subunits—designated A ([[Molecular mass|mol. wt.]] 32000 Da) and B (mol. wt. 7700 Da)—and is one of the [[AB5 toxin|AB<sub>5</sub> toxins]]. The B subunit is a [[oligomer|pentamer]] that binds to specific [[glycolipid]]s on the host cell, specifically [[globotriaosylceramide]] (Gb3).<ref name="pmid_1741063">{{cite journal | vauthors = Stein PE, Boodhoo A, Tyrrell GJ, Brunton JL, Read RJ | title = Crystal structure of the cell-binding B oligomer of verotoxin-1 from E. coli | journal = Nature | volume = 355 | issue = 6362 | pages = 748–50 | date = February 1992 | pmid = 1741063 | doi = 10.1038/355748a0 | bibcode = 1992Natur.355..748S | s2cid = 4274763 }}</ref><ref>{{cite journal | vauthors = Kaper JB, Nataro JP, Mobley HL | title = Pathogenic Escherichia coli | journal = Nature Reviews. Microbiology | volume = 2 | issue = 2 | pages = 123–40 | date = February 2004 | pmid = 15040260 | doi = 10.1038/nrmicro818 | s2cid = 3343088 }}</ref>   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 LD<sub>50</sub> 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]].<ref name=Obata_2008>{{cite journal | vauthors = Obata F, Tohyama K, Bonev AD, Kolling GL, Keepers TR, Gross LK, Nelson MT, Sato S, Obrig TG | title = Shiga toxin 2 affects the central nervous system through receptor globotriaosylceramide localized to neurons | journal = The Journal of Infectious Diseases | volume = 198 | issue = 9 | pages = 1398–406 | date = November 2008 | pmid = 18754742 | pmc = 2684825 | doi = 10.1086/591911 }}</ref>
Stx-2 is also known to increase the expression of its receptor GB3 and cause neuronal dysfunctions.<ref name=Tironi-Farinati_2010>{{cite journal | vauthors = Tironi-Farinati C, Loidl CF, Boccoli J, Parma Y, Fernandez-Miyakawa ME, Goldstein J | title = Intracerebroventricular Shiga toxin 2 increases the expression of its receptor globotriaosylceramide and causes dendritic abnormalities | journal = Journal of Neuroimmunology | volume = 222 | issue = 1–2 | pages = 48–61 | date = May 2010 | pmid = 20347160 | doi = 10.1016/j.jneuroim.2010.03.001 | s2cid = 11910897 | hdl = 11336/16303 | hdl-access = free }}</ref>