Editing Shiga toxin

{{short description|Family of related toxins}}
[[File:Shiga toxin (Stx) PDB 1r4q.png|thumb|[[Ribbon diagram]] of Shiga toxin (Stx) from ''S. dysenteriae''. From {{PDB|1R4Q}}.]]
{{Infobox protein family
| Symbol = SLT_beta 
| Name = Shiga-like toxin beta subunit 
| image =
| width = 
| caption = 
| Pfam= PF02258
| InterPro= IPR003189
| SMART= 
| Prosite =          
| SCOP = 2bos
| TCDB =  1.C.54
| OPM family= 
| OPM protein= 
| PDB=  
}} 
{{Infobox protein family
| Symbol = Shiga-like_toxin_subunit_A
| Name = Shiga-like toxin subunit A
| InterPro= IPR016331
| SMART= 
| Prosite =          
| SCOP = 1r4q
| OPM family= 
| OPM protein= 
| PDB=  
}}
 
'''Shiga toxins''' are a family of related [[exotoxin|toxins]] with two major groups, Stx1 and Stx2, expressed by genes considered to be part of the [[genome]] of [[Lambdavirus|lambdoid]] [[prophage]]s.<ref name=Friedman_2001>{{cite journal |author1=Friedman D |author2=Court D |title=Bacteriophage lambda: alive and well and still doing its thing |journal=Current Opinion in Microbiology |volume=4 |issue=2 |pages=201–7 |year=2001 |pmid=11282477 |doi=10.1016/S1369-5274(00)00189-2}}</ref>  The toxins are named after [[Kiyoshi Shiga]], who first described the bacterial origin of [[dysentery]] caused by ''[[Shigella dysenteriae]]''.<ref name=shiga-nom>{{Cite journal|last1=Trofa|first1=Andrew F.|last2=Ueno-Olsen|first2=Hannah|last3=Oiwa|first3=Ruiko|last4=Yoshikawa|first4=Masanosuke|date=1999-11-01|title=Dr. Kiyoshi Shiga: Discoverer of the Dysentery Bacillus|journal=Clinical Infectious Diseases|language=en|volume=29|issue=5|pages=1303–1306|doi=10.1086/313437|pmid=10524979|issn=1058-4838|doi-access=free}}</ref> '''Shiga-like toxin''' ('''SLT''') is a historical term for similar or identical toxins produced by ''[[Escherichia coli]]''.<ref name="pmid12123543">{{cite journal |author1=Zhu Q |author2=Li L |author3=Guo Z |author4=Yang R |title=Identification of Shiga-like toxin Escherichia coli isolated from children with diarrhea by polymerase chain reaction |journal=Chin. Med. J. |volume=115 |issue=6 |pages=815–8 |date=June 2002 |pmid=12123543 |url=http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2002&vol=115&issue=6&beginpage=815}}</ref> The most common sources for Shiga toxin are the bacteria ''S. dysenteriae'' and [[shigatoxigenic and verotoxigenic Escherichia coli|some serotypes]] of ''Escherichia coli'' (shigatoxigenic or STEC), which include [[serotype]]s [[Escherichia coli O157:H7|O157:H7]], and [[Escherichia coli O104:H4|O104:H4]].<ref name=Beutin_2006>{{cite journal |vauthors=Beutin L |title=Emerging enterohaemorrhagic Escherichia coli, causes and effects of the rise of a human pathogen |journal= Journal of Veterinary Medicine, Series B |volume=53 |issue=7 |pages=299–305 |year=2006 |pmid=16930272 |doi=10.1111/j.1439-0450.2006.00968.x}}</ref><ref>{{cite journal|vauthors=Spears KJ, Roe AJ, Gally DL|title=A comparison of enteropathogenic and enterohaemorragic ''Escherichia coli'' pathogenesis|journal=FEMS Microbiology Letters|year=2006|pages=187–202|doi=10.1111/j.1574-6968.2006.00119.x|pmid=16448495|volume=255|issue=2|doi-access=free}}</ref>

== Nomenclature ==
[[Microbiologists]] use many terms to describe Shiga toxin and differentiate more than one unique form.  Many of these terms [[synonym|are used interchangeably]].

# 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.<ref name="Kaper2014">{{cite journal|vauthors=Kaper JB, O'Brien AD |title=Overview and Historical Perspectives |journal=Microbiology Spectrum |volume=2 |issue=6 |veditors=Sperandio V, Hovde CJ|year=2014 |pmid=25590020 |pmc=4290666 |doi=10.1128/microbiolspec.EHEC-0028-2014}}</ref>  Stx-2 shares 55% amino acid homology with Stx-1.<ref>{{cite journal |last1=Kaper |first1=James B. |last2=Nataro |first2=James P. |last3=Mobley |first3=Harry L. T. |title=Pathogenic Escherichia coli |journal=Nature Reviews Microbiology |date=February 2004 |volume=2 |issue=2 |pages=123–140 |doi=10.1038/nrmicro818 |pmid=15040260 }}</ref>
# Cytotoxins – an archaic denotation for Stx – is used in a broad [[word sense|sense]].
# Verocytotoxins/verotoxins – a seldom-used term for Stx – is from the hypersensitivity of [[Vero cells]] to Stx.<ref name="pmid8408571">{{cite journal |author1=Beutin L |author2=Geier D |author3=Steinrück H |author4=Zimmermann S |author5=Scheutz F |title=Prevalence and some properties of verotoxin (Shiga-like toxin)-producing Escherichia coli in seven different species of healthy domestic animals |journal=Journal of Clinical Microbiology |volume=31 |issue=9 |pages=2483–8 |date=September 1993 |pmid=8408571 |pmc=265781 |doi= 10.1128/JCM.31.9.2483-2488.1993}}</ref><ref name="pmid8039905">{{cite journal |author1=Bitzan M |author2=Richardson S |author3=Huang C |author4=Boyd B |author5=Petric M |author6=Karmali MA |title=Evidence that verotoxins (Shiga-like toxins) from Escherichia coli bind to P blood group antigens of human erythrocytes in vitro |journal=Infection and Immunity |volume=62 |issue=8 |pages=3337–47 |date=August 1994 |pmid=8039905 |pmc=302964 |doi= 10.1128/IAI.62.8.3337-3347.1994}}</ref><ref name="pmid2199511">{{cite journal |author1=Giraldi R |author2=Guth BE |author3=Trabulsi LR |title=Production of Shiga-like toxin among Escherichia coli strains and other bacteria isolated from diarrhea in São Paulo, Brazil |journal=Journal of Clinical Microbiology |volume=28 |issue=6 |pages=1460–2 |date=June 1990 |pmid=2199511 |pmc=267957 |doi= 10.1128/JCM.28.6.1460-1462.1990}}</ref>
# The term Shiga-like toxins is another antiquated term which arose prior to the understanding that Shiga and Shiga-like toxins were identical.<ref>{{cite journal | vauthors = Scheutz F, Teel LD, Beutin L, Piérard D, Buvens G, Karch H, Mellmann A, Caprioli A, Tozzoli R, Morabito S, Strockbine NA, Melton-Celsa AR, Sanchez M, Persson S, O'Brien AD | title = Multicenter evaluation of a sequence-based protocol for subtyping Shiga toxins and standardizing Stx nomenclature | journal = Journal of Clinical Microbiology | volume = 50 | issue = 9 | pages = 2951–63 | date = September 2012 | pmid = 22760050 | pmc = 3421821 | doi = 10.1128/JCM.00860-12 }}</ref>

==History==
The toxin is named after [[Kiyoshi Shiga]], who discovered ''S. dysenteriae'' in 1897.<ref name=shiga-nom/> In 1977, researchers in [[Ottawa, Ontario]] discovered the Shiga toxin normally produced by ''[[Shigella dysenteriae]]'' in a line of ''E. coli''.<ref>{{cite journal | vauthors = Konowalchuk J, Speirs JI, Stavric S | title = Vero response to a cytotoxin of Escherichia coli | journal = Infection and Immunity | volume = 18 | issue = 3 | pages = 775–9 | date = December 1977 | doi = 10.1128/IAI.18.3.775-779.1977 | pmid = 338490 | pmc = 421302 }}</ref> The ''E. coli'' version of the toxin was named "verotoxin" because of its ability to kill [[Vero cell|''Vero'' cells]] ([[Chlorocebus|African green monkey]] [[kidney]] cells) in culture.  Shortly after, the verotoxin was referred to as Shiga-like toxin because of its similarities to Shiga toxin.

It has been suggested by some researchers that the gene coding for Shiga-like toxin comes from a toxin-converting lambdoid [[bacteriophage]], such as H-19B or 933W, inserted into the [[bacteria|bacteria's]] [[chromosome]] via [[transduction (genetics)|transduction]].<ref>{{cite journal | vauthors = Mizutani S, Nakazono N, Sugino Y | title = The so-called chromosomal verotoxin genes are actually carried by defective prophages | journal = DNA Research | volume = 6 | issue = 2 | pages = 141–3 | date = April 1999 | pmid = 10382973 | doi = 10.1093/dnares/6.2.141 | doi-access = free }}</ref> [[Phylogenetic]] studies of the [[Escherichia coli#Diversity|diversity of ''E. coli'']] suggest that it may have been relatively easy for Shiga toxin to transduce into certain strains of  ''E. coli'', because ''[[Shigella]]'' is itself a [[subgenus]] of ''[[Escherichia]]''; in fact, some strains traditionally considered ''E. coli'' (including those that produce this toxin) in fact belong to this lineage. Being closer relatives of ''Shigella dysenteriae'' than of the [[type strain|typical]] ''E. coli'', it is not at all unusual that toxins similar to that of ''S. dysenteriae'' are produced by these strains. As microbiology advances, the historical variation in nomenclature (which arose because of gradually advancing science in multiple places) is increasingly giving way to recognizing all of these molecules as "versions of the same toxin" rather than "different toxins".<ref name="Silva_et_al_2017">{{Citation |last1=Silva |first1=Christopher J. |last2=Brandon |first2=David L. |last3=Skinner |first3=Craig B. |last4=He |first4=Xiaohua |display-authors=etal | name-list-style = vanc |year=2017 |title=Shiga toxins: A Review of Structure, Mechanism, and Detection |chapter=Chapter 3: Structure of Shiga toxins and other AB5 toxins |publisher=Springer|chapter-url=https://books.google.com/books?id=nKQ7DgAAQBAJ&q=%22verocytotoxin+VCT%22&pg=PA22 |isbn=978-3319505800 |postscript=.}}</ref>{{rp|2–3}}

==Transmission==
The toxin requires highly specific [[receptor (biochemistry)|receptor]]s on the cells' surface in order to attach and enter the [[cell (biology)|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.<ref name=Asakura_2001>{{cite journal |last1=Asakura |first1=H. |last2=Makino |first2=S-I. |last3=Kobori |first3=H. |last4=Watarai |first4=M. |last5=Shirahata |first5=T. |last6=Ikeda |first6=T. |last7=Takeshi |first7=K. |title=Phylogenetic diversity and similarity of active sites of Shiga toxin (Stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals |journal=Epidemiology and Infection |date=April 2001 |volume=127 |issue=1 |pages=27–36 |doi=10.1017/s0950268801005635 |doi-broken-date=1 November 2024 |pmid=11561972 |pmc=2869726 }}</ref>

==Clinical significance==
Symptoms of Shiga toxin ingestion include abdominal pain as well as watery diarrhea. Severe life-threatening cases are characterized by [[colitis|hemorrhagic colitis]] (HC).<ref>{{cite journal |last1=Beutin |first1=Lothar |last2=Miko |first2=Angelika |last3=Krause |first3=Gladys |last4=Pries |first4=Karin |last5=Haby |first5=Sabine |last6=Steege |first6=Katja |last7=Albrecht |first7=Nadine |title=Identification of Human-Pathogenic Strains of Shiga Toxin-Producing Escherichia coli from Food by a Combination of Serotyping and Molecular Typing of Shiga Toxin Genes |journal=Applied and Environmental Microbiology |date=August 2007 |volume=73 |issue=15 |pages=4769–4775 |doi=10.1128/AEM.00873-07 |pmid=17557838 |pmc=1951031 |bibcode=2007ApEnM..73.4769B }}</ref>

The toxin is associated with [[hemolytic-uremic syndrome]]. In contrast, ''Shigella'' species may also produce [[shigella enterotoxins]], which are the cause of [[dysentery]].

The toxin is effective against small blood vessels, such as found in the [[digestive tract]], the [[kidney]], and [[lungs]], but not against large vessels such as the [[arteries]] or major [[veins]]. A specific target for the toxin appears to be the vascular endothelium of the [[Glomerulus (kidney)|glomerulus]]. This is the filtering structure that is a key to the function of the kidney. Destroying these structures leads to kidney failure and the development of the often deadly and frequently debilitating hemolytic uremic syndrome. [[Food poisoning]] with Shiga toxin often also has effects on the lungs and the [[nervous system]].

==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>

== See also ==
* [[2011 German E. coli outbreak|2011 German ''E. coli'' outbreak]]
* [[Cholera toxin]]
* [[Enterotoxin]]
* [[Pertussis toxin]]

== References ==
{{Reflist|30em}}

== External links ==
* UniprotKB entries: stxA1 {{uniprot|Q9FBI2}}, stxB1 {{uniprot|Q7BQ98}}, stxA2 {{uniprot|P09385}}, stxB2 {{uniprot|P09386}}
* {{MeshName|Shiga+toxin}}
* {{MeshName|Shiga-Like+Toxin+I}}
* {{MeshName|Shiga-Like+Toxin+II}}
* [http://www.textbookofbacteriology.net/Shigella.html "Shigella"] in ''Todar's Online Textbook of Bacteriology''
* {{cite journal |last1=Mizutani |first1=S. |title=The So-called Chromosomal Verotoxin Genes are Actually Carried by Defective Prophages |journal=DNA Research |date=1999 |volume=6 |issue=2 |pages=141–143 |doi=10.1093/dnares/6.2.141 |pmid=10382973 }}

{{Toxins}}

[[Category:AB5 toxins]]
[[Category:Bacterial toxins]]
[[Category:Biological toxin weapons]]
[[Category:Ribosome-inactivating proteins]]
[[Category:Invertebrate toxins]]
[[Category:Microbiology]]