Scientists Discover Toxin That Causes Gastro Disease
Main Category: GastroIntestinal / Gastroentorology News
Article Date: 11 Oct 2006 - 21:00pm (PDT)



Australian scientists have identified a highly potent toxin that causes severe gastrointestinal illnesses, including food poisoning.

The toxin, produced by certain strains of E. coli bacteria, has been found to be responsible for an outbreak of haemolytic uraemic syndrome, a dangerous disease that causes acute kidney failure, in South Australia in 1998.

The research team was led by Dr Adrienne Paton from the University of Adelaide, and included scientists from Monash University's ARC Centre of Excellence in Structural and Functional Microbial Genomics, and the United States.

Dr Travis Beddoe from Monash University's Department of Biochemistry and Molecular Biology, is one of the investigators who discovered that the bacterial toxin, subtilase cytotoxin, deactivates an essential component of cells in the gastrointestinal tract.

"It is unique because it cuts an essential component of the cell machinery in half, therefore disabling it," he said.

As well as learning how the toxin works, the scientists have also determined its three-dimensional structure, which will aid in the development of treatments for toxin-related diseases.

"This toxin belongs to the family of toxins that cause whooping cough, a very serious bacterial infection that affects children," Dr Beddoe said.

He said the research breakthrough may also provide insights into the development of age-related and degenerative diseases such as Parkinson's disease and Alzheimer's disease, and may be used in the treatment of some cancers.

The collaborative research was supported by the National Health and Medical Research Council and the Australian Research Council. The research findings are published in the latest issue of the journal Nature.

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Nature 443, 548-552(5 October 2006) | doi:10.1038/nature05124; Received 23 May 2006; Accepted 1 August 2006
AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP

From the article:

"AB5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli.

Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity.

A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death."


Discussion

The findings of this study indicate that SubAB is unique in two ways. Unlike other bacterial AB5 cytotoxins, it does not need to be translocated from the ER lumen into the cytosol in order to interact with its cellular target. For Ctx and Stx, this retro-translocation is achieved through subversion of the Sec61 translocon apparatus, which is normally used to transport terminally misfolded host proteins from the ER lumen into the cytosol for degradation, a process in which BiP is also involved15, 16.

Most importantly, however, no other cytotoxin has been shown to target chaperone proteins or components of the ER directly.

Defects in chaperone function, particularly those that affect ER stress responses, have been implicated in cellular senescence and a range of degenerative conditions including cataracts and Parkinson's and Alzheimer's diseases6, 17. Through its ability to rapidly and specifically abolish BiP function, SubAB provides a new tool in cell biology that enables in vitro modelling of key events in the pathogenesis of these diseases.

BiP is a highly conserved master regulator of ER function, and is essential for survival of eukaryotes from simple yeasts to higher organisms such as mammals6, 7. There is negligible sequence variation in the vicinity of the cleavage site, indicating that SubAB has the potential for toxicity against a broad spectrum of life forms. Our findings reveal a previously undescribed mechanism of inducing cell death, through the specific targeting of a protease to disable chaperone function.