A powerful plant toxin widely feared for its bioterrorism potential may one day be tamed using findings about how the toxin attacks cells. The findings may also help scientists combat food poisoning episodes such as those recently caused by bacteria-tainted produce and ground meat.
Biotechnology researchers at Rutgers University have discovered that ricin, extracted from abundant castor beans, kills cells by a previously unrecognized activity that appears to work in concert with its ability to damage protein synthesis. While those earlier known effects still harm cells, it’s the newly discovered and more stealthy activity that the researchers now believe delivers the knockout punch.
Ricin toxin is feared as a bioterror agent because it can be easily purified from the waste of castor oil production and there are no known antidotes. It is poisonous if inhaled, ingested or injected. Symptoms can show up within hours, including difficulty breathing, nausea, vomiting and diarrhea. Death can result within days from low blood pressure, severe dehydration, respiratory failure and eventually, failure of organs such as the liver and kidneys. Those who survive severe ricin poisoning may still have permanent or long-lasting organ damage.
Writing in the March 7 issue of the Journal of Biological Chemistry, Rutgers plant biology and pathology professor Nilgun Tumer and her colleagues report that ricin tricks a cell into turning off a natural defense mechanism that destroys foreign proteins. If ricin did not first deactivate the cell’s defenses, the cell would be able to turn on a stress response to get rid of the toxin. The discovery allows scientists to explore new ways to disarm ricin.
“Because there are no specific medical treatment options for ricin intoxication, we felt it essential to dig deeper into the mechanism of ricin-induced cell death,” said Tumer. “The new mechanism we discovered provides new targets for possible therapeutic agents.”
Tumer discovered that ricin is inhibiting a cell defense mechanism known as unfolded protein response or UPR. Proteins that a cell synthesizes need to have their long molecular chains folded in a precise pattern. The UPR causes proteins that don’t fold, or that fold incorrectly, to be degraded and removed from the place in a cell where folding occurs, known as the endoplasmic reticulum (ER).
When the toxic ricin A protein enters a cell, it takes a reverse pathway, being transported to and unfolded in the ER. At this point, the UPR should initiate a cell stress response that degrades the unfolded proteins, hence acting as the cell’s first line of defense. A piece of the ricin A protein molecule, however, signals the ER to shut down its UPR and the cell’s stress response needed for survival.
Tumer verified this mechanism by testing it with a mutant form of the ricin A protein molecule. The mutant lacked the signal that caused the UPR to shut down. When Tumer introduced the mutant protein into yeast cells, she found that the UPR triggered the necessary stress response.
“At first, we thought ricin might be triggering the stress response and preventing it from turning off, which causes cell damage in some cancers and type II diabetes,” Tumer said. But in experiments with the mutant form of ricin A protein, the stress response was turning on and off properly. “Then we discovered that the wild ricin A protein was inhibiting the stress response,” she said.
Tumer noted that toxins secreted by some strains of E. coli bacteria, including those blamed for high-profile food poisoning cases recently involving spinach, lettuce and fast-food hamburgers, appear to have a similar mechanism to ricin. Further study is needed to verify this and find ways to combat the toxin.
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