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Bubonic Plague Kills By Cutting Off Cellular Communication

Date:
September 17, 1999
Source:
University Of Michigan
Summary:
Yersinia pestis, the deadly bacterium that causes bubonic plague, kills by cutting off a cell's ability to communicate with other immune system cells needed to fight off the bacterial invasion. University of Michigan scientists identify one protein responsible for the plague's lethal effect and the molecular family it targets.

One molecule holds the key to plague's lethal effects.

Contact: Sally Pobojewski
Phone: (734) 647-1844
E-mail: pobo@umich.edu

ANN ARBOR --- Yersinia pestis, the deadly bacterium that causes bubonic plague, kills by cutting off a cell's ability to communicate with other immune system cells needed to fight off the bacterial invasion. In a study published in the Sept. 17 issue of Science, University of Michigan scientists identify one protein responsible for the plague's lethal effect and the molecular family it targets.

"Yersinia is a clever pathogen," says Kim Orth, Ph.D., a research investigator in the U-M Medical School. "It found our Achilles heel --- one family of molecules used by every mammalian cell to transmit signals involved in the immune response and cell death."

If scientists can understand the mechanism Yersinia uses to control cell signaling and how it destroys the immune communications system, it could have important implications in medicine, especially in cancer and immune-related diseases, Orth adds.

"YopJ, the protein Yersinia uses to block this signaling process, is one of six proteins injected by the bacteria into immune cells called macrophages," says Jack E. Dixon, the Minor J. Coon Professor of Biological Chemistry in the U-M Medical School, who directed the research. Every Yop has a specific function and they work together to gain entry into a cell and destroy the body's defense systems.

"In this study, we found that YopJ binds to similar molecules located at the same point in two critical cellular signaling pathways," Dixon says.

The first pathway, called MAPK, controls cell growth and regulates the immune inflammatory response. The second pathway, known as NF(B, also regulates the immune inflammatory response, as well as preventing cell death and controlling embryonic development.

"Scientists thought these two pathways were unrelated, but YopJ recognized a common component in molecules at the mid-point of the MAPK and NF(B pathways," Orth says. "By binding to this one molecule, called MKK in one pathway and IKKbeta in the other, YopJ cuts the main cellular communications cable and shuts down signaling."

Once scientists understand exactly how YopJ binds to and disables MKK and IKKbeta, it should be possible to identify the docking site on this entire superfamily of molecules, which would be an important target for future drug design.

U-M scientists used a yeast two-hybrid screen to determine that YopJ targets all members of the MKK family in mammalian cells, but not other proteins in the MAPK pathway. Additional experiments revealed that the targeted molecule in the NF(B pathway was IKKbeta. Later experiments with mouse macrophages infected with Yersinia showed that YopJ prevented other kinases from activating MKK.

"Because YopJ is found in many species of bacteria --- including Salmonella, an intestinal pathogen, and Rhizobium, symbiotic bacteria involved in nitrogen fixation, it is particularly intriguing," Dixon says. "It is rare that a protein effector is found in both plant and animal pathogens.

"YopJ's molecular structure is slightly different in other bacterial species and it attacks different types of cells, but all YopJ proteins undoubtedly recognize the same molecule in the MAPK pathway," Dixon says. "This indicates YopJ is an important and effective virulence factor, which has been conserved for long periods of evolutionary history."

The study was funded by the National Institutes of Health and the Walther Cancer Institute. Collaborators on the study from the U-M Medical School included Zhao Qin Bao, U-M research associate; Scott Stewart, a U-M graduate student and Amy E. Rudolph, Ph.D., a U-M post-doctoral research fellow. Additional collaborators were James B. Bliska, Ph.D., and graduate student Lance E. Palmer from the State University of New York at Stony Brook.


Story Source:

The above story is based on materials provided by University Of Michigan. Note: Materials may be edited for content and length.


Cite This Page:

University Of Michigan. "Bubonic Plague Kills By Cutting Off Cellular Communication." ScienceDaily. ScienceDaily, 17 September 1999. <www.sciencedaily.com/releases/1999/09/990916134550.htm>.
University Of Michigan. (1999, September 17). Bubonic Plague Kills By Cutting Off Cellular Communication. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/1999/09/990916134550.htm
University Of Michigan. "Bubonic Plague Kills By Cutting Off Cellular Communication." ScienceDaily. www.sciencedaily.com/releases/1999/09/990916134550.htm (accessed October 23, 2014).

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