When cornered by immune system seek-and-destroy cells called macrophages, Yersinia bacteria--the culprits behind the plague and other diseases--fight back viciously. Like a poisonous snake, the bacteria inject a toxin that rapidly paralyzes the macrophages. Now scientists have located the signal that the bacteria uses to unleash its toxin. The finding, reported in tomorrow's Science , could lead to better antibiotics or new ways to deliver therapeutic proteins.
The proteins that bacteria secrete are labeled with unique amino acid sequences, which tell the cells that the proteins are destined for secretion. Although Yersinia's molecular syringe for shooting up macrophages was discovered 4 years ago, scientists couldn't figure out how the bacteria knew what to load into it; the toxins, called Yersinia outer proteins (Yops), had no apparent amino acid signal for secretion.
To try to find the signal, Olaf Schneewind and his colleagues at the University of California School of Medicine in Los Angeles looked at the genes for two proteins called YopE and YopN. They found that the initial stretch of either gene coded for the part of the protein that was necessary for secretion. But oddly, the secretion still took place even when they drastically mutated the gene--a resilience not found in any known secretion signal.
The researchers suspected, therefore, that the bacteria must be using a completely novel signal. Instead of being embedded in the protein itself, they guessed that the command must be in messenger RNA (mRNA), the template for assembling the protein. To check, the team added one type of radioactively labeled amino acid to the bacteria, and almost immediately the bacteria began to secrete YopE proteins that contained the radioactive amino acid. This synchronicity, say the researchers, suggests that the mRNA is a crucial player in secretion of the Yop protein.
"The consequences of this prediction are remarkable," comments Thomas Silhavy, a molecular biologist at Princeton University. Knowing how Yersinia secretes its toxins could lead to novel drugs to fight the bacteria. And biotech firms might someday be able to exploit these bacteria as miniature factories for injecting proteins directly into human cells.