Cholera toxin

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=== How CT Causes Disease  ===
 
=== How CT Causes Disease  ===
  
Following the toxins entry into the cell and Alpha protomer cleavage, the A1 is trafficked to the&nbsp;[[Endoplasmic reticulum|endoplasmic reticulum]]&nbsp;(ER) where it associates with disulphide isomerase (PDI). This triggers the unfolding of the A1 chain and consequently allows it to hijack the ER association degradation mechanism to enter the cytosol by retro-translocation. Normally, proteins which enter the cytosol in this manner are ubiquitinated and then degraded by the proteasome, however, the A1 subunit avoids this fate by rapid refolding<ref>Naomi L. B. Wernick, D. J.-F. C. A. C. a. W. I. L., 2010. Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic Reticulum. MDPI, 2(3), pp. 310-325.</ref>.<br>  
+
Following the toxins entry into the cell and Alpha protomer cleavage, the A1 is trafficked to the&nbsp;[[Endoplasmic reticulum|endoplasmic reticulum]]&nbsp;(ER) where it associates with disulphide [[Isomerase|isomerase]] (PDI). This triggers the unfolding of the A1 chain and consequently allows it to hijack the ER association degradation mechanism to enter the cytosol by retro-translocation. Normally, proteins which enter the cytosol in this manner are ubiquitinated and then degraded by the proteasome, however, the A1 subunit avoids this fate by rapid refolding<ref>Naomi L. B. Wernick, D. J.-F. C. A. C. a. W. I. L., 2010. Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic Reticulum. MDPI, 2(3), pp. 310-325.</ref>.<br>  
  
The A1 can now ribosylates the alpha subunit of a [[G-protein|G-protein]] associated with an intestinal [[Epithelial Cells|epithelial]] cell, preventing the [[Hydrolysis|hydrolysis]] of [[GTP|GTP]] bound to the same G-protein. This locks the G-protein in an active state, leading to the indefinite stimulation of [[Adenyl cyclase|adenylyl cyclase]], causing a rise in [[CAMP|cAMP]] [[Concentration|concentration]]. This causes phosphorylation and activation of the cystic fibrosis transmembrane conductance regulator (CFTR protein) leading to &nbsp;the ATP mediated efflux of chloride ions&nbsp;pumped out of the enterocyte. <ref>Wayne I. Lencer, T. R. H. R. K. H., 1999. Membrane traffic and the cellular uptake of cholera toxin. Biochimica et Biophysica Acta (BBA), 1450(3), pp. 177-190.</ref>This then causes water, sodium and potassium to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea<ref>Bruce Alberts, A. J. J. L. M. R. K. R. a. P. W., 2007. Molecular Biology of the Cell, 5th edition. In: Molecular Biology of the Cell, 5th edition. New York: Garland Science, p. 906.</ref>. This is due to the water potential being dratically lowered in the lumen due to the eflux of [[Ions|ions]]. Water therefore flows out of the [[Epithelial Cells|epithelial cells]] surrounding the [[Small intestine|small intestine]], and into the lumen.&nbsp;  
+
The A1 can now ribosylates the alpha subunit of a [[G-protein|G-protein]] associated with an intestinal [[Epithelial Cells|epithelial]] cell, preventing the [[Hydrolysis|hydrolysis]] of [[GTP|GTP]] bound to the same G-protein. This locks the G-protein in an active state, leading to the indefinite stimulation of [[Adenyl cyclase|adenylyl cyclase]], causing a rise in [[CAMP|cAMP]] [[Concentration|concentration]]. This causes [[Phosphorylation|phosphorylation]] and activation of the cystic fibrosis transmembrane conductance regulator (CFTR protein) leading to &nbsp;the ATP mediated efflux of chloride ions&nbsp;pumped out of the enterocyte. <ref>Wayne I. Lencer, T. R. H. R. K. H., 1999. Membrane traffic and the cellular uptake of cholera toxin. Biochimica et Biophysica Acta (BBA), 1450(3), pp. 177-190.</ref>This then causes water, [[Sodium|sodium]] and [[Potassium|potassium]] to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea<ref>Bruce Alberts, A. J. J. L. M. R. K. R. a. P. W., 2007. Molecular Biology of the Cell, 5th edition. In: Molecular Biology of the Cell, 5th edition. New York: Garland Science, p. 906.</ref>. This is due to the water potential being dratically lowered in the lumen due to the eflux of [[Ions|ions]]. Water therefore flows out of the [[Epithelial Cells|epithelial cells]] surrounding the [[Small intestine|small intestine]], and into the lumen.&nbsp;
  
 
=== References  ===
 
=== References  ===
  
 
<references />
 
<references />

Revision as of 12:27, 28 November 2014

Contents

Introduction

Cholera Toxin (CT or CTX) is a protein enterotoxin, secreted by toxic species of the the bacterium Vibrio choleraeUNIQ7ee6d88b591479d8-nowiki-00000001-QINU1UNIQ7ee6d88b591479d8-nowiki-00000002-QINU. CT is transmitted between patients via the fecal-oral route and is often found in countries with poor sanitation. CT is characterised by its ability to cause severe diarrhoea, often leading to dehydration[2].

Structure of the Toxin 

CT is a member of the AB5 family of toxins and consists of subunits, Alpha and 5 Beta. The five Beta subunits are arranged into a pentameric ring and are responsible for binding the toxin to a cell's membrane[3], weighing 11kDa each, binds to five ganglioslide GM1 receptors on the plasma membrane and trigers endocytosis of the toxin, whilst the Alpha subunit is made up of an A1 and A2 chain. A1 is enzymatic and does most of the work, once inside the cell. A2 is an extended alpha helix, connceting the alpha subunit to the Beta subunit. The alpha subunit is cleaved apart once inside the cell, allowing the A1 chain to dissociate and begin its catalytic activity, leaving the A2 domain which had been anchoring the A1 chain to the Beta subunit[4].  

Mechanism of Infection

The location of CTX’s function is found in the lumen of the small intestine[5], where, in an effort to infect cells, the bacterium vibrio cholerae produces an invasin[6]. The gastrointestinal (GI) tract is coated with a mucus lining with the aim to prevent pathogens such as CT from entering the endothelial cells of the gut lining[7].
Cholera Toxin entering cell membrane via GM1.
[8]

Neuraminidase is produced by cholera cells as an invasin, neuraminidase is part of a group of enzymes responsible for removing the carbohydrate sialic acid[9] from the surface membranes of GI cells, this overrides the GI tract’s mucus defence and allows the B subunit to bind to the glycolipid monosialosyl ganglioside (GM1): the receptor of CTX[10].

Once the binding of the B subunit is complete with GM1, the role of this part of the CTX is relatively complete. CTA1 is subsequently able to enter the cell, passing through the membrane.

How CT Causes Disease

Following the toxins entry into the cell and Alpha protomer cleavage, the A1 is trafficked to the endoplasmic reticulum (ER) where it associates with disulphide isomerase (PDI). This triggers the unfolding of the A1 chain and consequently allows it to hijack the ER association degradation mechanism to enter the cytosol by retro-translocation. Normally, proteins which enter the cytosol in this manner are ubiquitinated and then degraded by the proteasome, however, the A1 subunit avoids this fate by rapid refolding[11].

The A1 can now ribosylates the alpha subunit of a G-protein associated with an intestinal epithelial cell, preventing the hydrolysis of GTP bound to the same G-protein. This locks the G-protein in an active state, leading to the indefinite stimulation of adenylyl cyclase, causing a rise in cAMP concentration. This causes phosphorylation and activation of the cystic fibrosis transmembrane conductance regulator (CFTR protein) leading to  the ATP mediated efflux of chloride ions pumped out of the enterocyte. [12]This then causes water, sodium and potassium to leave the cell and enter the intestinal lumen, leading to the severe diarrhoea[13]. This is due to the water potential being dratically lowered in the lumen due to the eflux of ions. Water therefore flows out of the epithelial cells surrounding the small intestine, and into the lumen. 

References

  1. Vanden Broeck D, H. C. D. W. M., 2007. Vibrio cholerae: cholera toxin. Int J Biochem Cell Biol, 39(10), pp. 1771-1775.
  2. Dilip Kumar Biswas, Rama Bhunia, Dipankar Maji, and Palash Das, “Contaminated Pond Water Favors Cholera Outbreak at Haibatpur Village, Purba Medinipur District, West Bengal, India,” Journal of Tropical Medicine, vol. 2014, Article ID 764530, 5 pages, 2014. doi:10.1155/2014/764530
  3. Haan, L. and Hirst, T. 2004. Cholera toxin: A paradigm for multi-functional engagement of cellular mechanisms. From Molecular Membrane Biology: Vol. 21/2 pp77-92 [Journal Article]fckLRAvailable at http://informahealthcare.com/doi/abs/10.1080/09687680410001663267 (Accessed 17/11/14)
  4. Daniel J.-F. Chinnapen, H. C. D. S. W. I. L., 2006. Rafting with cholera toxin: endocytosis and trafficking from plasma membrane to ER. FEMS Microbiology Letters, 266(2), pp. 129-137.
  5. Wellcome Trust. No Date. The biology behind Cholera. [Online]fckLRAvailable at http://bigpictureeducation.com/biology-behind-cholera
  6. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online]fckLRAvailable at http://textbookofbacteriology.net/cholera.html
  7. Palumbo, RN. and Wang, C. 2006. Bacterial invasin: structure, function, and implication for targeted oral gene delivery. From Current Drug Delivery: Vol. 3/1 pp47-53 [Journal Article]fckLRAvailable at http://www.ncbi.nlm.nih.gov/pubmed/16472093
  8. Edited version of CTA1 hydrolysis prevention of GTP to hide Pertussis Toxin - an alternative enterotoxin from Gill and Woolkalis, 1985
  9. Rogers, K. 2009. Neuraminidase. [Encyclopaedia]fckLRAvailable at http://www.britannica.com/EBchecked/topic/1093141/neuraminidase
  10. Todar, K. 2008. Vibrio cholerae and Asiatic Cholera [Online]fckLRAvailable at http://textbookofbacteriology.net/cholera.html
  11. Naomi L. B. Wernick, D. J.-F. C. A. C. a. W. I. L., 2010. Cholera Toxin: An Intracellular Journey into the Cytosol by Way of the Endoplasmic Reticulum. MDPI, 2(3), pp. 310-325.
  12. Wayne I. Lencer, T. R. H. R. K. H., 1999. Membrane traffic and the cellular uptake of cholera toxin. Biochimica et Biophysica Acta (BBA), 1450(3), pp. 177-190.
  13. Bruce Alberts, A. J. J. L. M. R. K. R. a. P. W., 2007. Molecular Biology of the Cell, 5th edition. In: Molecular Biology of the Cell, 5th edition. New York: Garland Science, p. 906.
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