The scientists, led by Dr Adrienne Paton from the University of Adelaide’s School of Molecular and Biomedical Science, have discovered that a highly potent bacterial toxin kills cells by inactivating an essential component in the endoplasmic reticulum (ER). The latter is part of the cell that is essential for packaging newly synthesized proteins.
The toxin, called subtilase cytotoxin, is produced by certain strains of E. coli bacteria responsible for severe gastrointestinal disease in humans. Dr Paton discovered the toxin in 2003 in a bacterium responsible for an outbreak of hemolytic uraemic syndrome (severe food poisoning) in South Australia. Subtilase cytotoxin is so potent that it is a potential bio-terrorism agent. Dr Paton and her colleagues published their findings today in Nature, the prestigious international weekly scientific journal.
“The ER is a command center of the cells of higher organisms, second only to the nucleus in its influence on other cellular functions. The molecule targeted by the toxin is a chaperone protein called BiP, which is a master regulator of ER function. Disrupting this crucially important chaperone has inevitably fatal consequences for a wide range of cell types,” stated Dr Paton.
As well as learning how the toxin works, the scientists have also determined its three-dimensional structure, which will help in the development of treatments for toxin-related diseases.
Dr Paton says the breakthrough may also provide insights into the development of age-related and degenerative diseases such as Parkinson’s disease and Alzheimer’s disease, which involve defects in ER function.
Scientific colleagues working on the discovery with Dr Paton included fellow researchers from the University of Adelaide, Professor James Paton and Ursula Talbot; Dr Celeste Thorpe from Tufts New England Medical Center in Boston; and Professor Jamie Rossjohn, Dr Travis Beddoe, Dr Matthew Wilce and Dr James Whisstock from Monash University.
Dr Beddoe stated, “This is a great example of Australian scientists collaborating to address important and timely biological problems. We had to use a combination of techniques, including that of synchrotron radiation, to unravel the secrets of the toxin.”