Cell Signaling and the Immune System:
A Protein Produced by the Bubonic Plague Bacterium Provides Intriguing Hints as to How the Body’s Defenses Are Destroyed

Yersinia pestis: No Friend to Man
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 September 17, 1999, issue of Science, U-M Medical School scientists identify one protein responsible for the plague’s lethal effect and the molecular family it targets.

Zhao Qin Bao and Kim Orth

“Yersinia is a clever pathogen,” says Kim Orth, Ph.D., a research investigator in the 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,” explains Jack E. Dixon, the Minor J. Coon Professor of Biological Chemistry and chair of the Department of Biological Chemistry, 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 NFkB, 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 NFkB 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.”

“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 molecules in the signaling pathways,” 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 Medical School included Zhao Qin Bao, research associate; Scott Stewart, a graduate student; and Amy E. Rudolph, Ph.D., a 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.

Orth can be reached at kimorth@umich.edu.