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November 23, 2000

Scientists Reveal How Germs Disrupt Cells' Distress Signals

Deadly mechanism, shared by plant and animal pathogens, may yield target for new drugs.

UPTON, NY - Scientists studying the germs that cause the Black Plague, plant infections, and colds have discovered that these three very different microorganisms share a common strategy: They all prevent the cells they're attacking from calling out for help. In a paper appearing in the November 24 issue of Science, the scientists describe how all three organisms produce a similar protein to interfere with the infected cells' chemical signaling pathways, which are designed to alert the immune system to attack the germs.

"Who would have predicted that these three, diverse pathogens would use the same protein to disrupt the same pathways to disable cell functions?" asks biologist Walter Mangel of the U.S. Department of Energy's Brookhaven National Laboratory, one of the collaborators. Understanding this common mechanism may provide scientists with a new target for combatting infections. The work may also provide insight into how cells communicate in diseases such as cancer.

Mangel and Brookhaven biologist William McGrath began investigating an enzyme from adenovirus, a cold virus, in 1991. They showed that this enzyme was unique in its genetic sequence and its three-dimensional structure (as determined at Brookhaven's National Synchrotron Light Source). They postulated that four crucial amino acids in the enzyme's active site gave it its ability to cleave proteins, an essential step in infecting cells.

Then, one day last year, Mangel received an e-mail from Jack Dixon, a microbiologist at the University of Michigan, who knew about Mangel's research and believed he was working with a similar enzyme. This enzyme was produced by Yersinia, the bacteria that cause the Black Death, or plague.

A model of the structure of the protein-cutting enzyme produced by adenovirus, a cold virus, which was determined at Brookhaven's NSLS. This enzyme shares four crucial amino acids (in yellow) with enzymes produced by microorganisms that cause the plague and some plant infections.

 

Dixon had already shown that the Yersinia enzyme, called YopJ, interrupted key signaling pathways in infected cells, effectively disabling the host's immune response. But he wasn't sure how it worked. If YopJ is similar to the adenovirus enzyme, he reasoned, those four amino acids crucial to the adenovirus enzyme should also be crucial to YopJ.

To test this hypothesis, Dixon mutated each of the four amino acids. None of the four mutants of YopJ was able to block the immune response. This showed that the four critical amino acids are essential to YopJ's ability to disrupt the cells' signaling pathways.

And, it turns out, adenovirus and Yersinia are not alone. Homologous enzymes produced by plant pathogens and plant symbionts (microbes that "infect" but live in harmony with plant cells), have the same arrangement of the four critical amino acids. This work was done by scientists at Michigan and the University of California at Berkeley.

"All these data strongly suggest that, like the adenovirus enzyme, YopJ and the enzymes of the plant pathogens are acting as proteinases, enzymes that cleave proteins, to disrupt universal cell signaling pathways," Mangel says.

The findings may be useful in medicine. "Knowing how cells communicate with each other should allow the development of means to prevent communication, for example to prevent cancer cells from communicating with each other," adds Mangel. "And if cancer cells can't talk to one another, they might not be able to grow into tumors."

Already, Mangel's laboratory has synthesized drugs that inhibit adenovirus proteinase. "It will be interesting to see what these drugs do with the Yersinia and the plant pathogens," he says.

The study was funded by the National Institutes of Health, the U.S. Department of Energy, and the Walther Cancer Institute. The State University of New York at Stony Brook was an additional collaborator.

The U.S. Department of Energy's Brookhaven National Laboratory creates and operates major facilities available to university, industrial and government personnel for basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. The Laboratory is operated by Brookhaven Science Associates, a not-for-profit research management company, under contract with the U.S. Department of Energy.

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Note to local editors: Walter Mangel lives in Shoreham, New York.

For U. of Michigan scientists, contact Sally Pobojewski, (734) 647-1844, pobo@umich.edu. For U.C. Berkeley scientists, contact Catherine Zandonella, (510) 643-7741, CLZ@pa.urel.berkeley.edu.