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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