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Scientists Identify Key Protein in Inflammasome Pathway


Research led by Giulio Superti-Furga, director of the Center for Molecular Medicine of the Austrian Academy of Sciences, and a postdoc in his lab, Tilmann Bürckstümmer, has found a key protein in the innate immune response pathway called the inflammasome. They discovered AIM2 to be a cytoplasmic sensor of invading DNA, possibly from a virus or pathogen. AIM2 turns out to be the missing link between the activation of interferon and the downstream interleukin signaling cascade, according to their study, which appeared in Nature Immunology.

"We found that many proteins were involved in the recognition of nucleic acids, but then there are viruses and bacteria that make it all the way into the cytoplasm, and they need to be at least identified before they create more havoc in the organism," Superti-Furga says. "So the question is, how do I know that this is a foreign element? There are a set of proteins that have evolved to do so."

When a cell encounters an invading pathogen — exogenous DNA in the form of an invading virus, for example — this foreign substance will trigger the transcriptional activation of interferon-β, which will then turn on the interleukin-1β response. "[The] interferon-b pathway is thought to prime the cell so that [it's] more susceptible," says Superti-Furga. "The interferon is there to create the first state of alertness, and then only if the problem persists [will] you get this strong and potentially much more cumbersome interleukin-1 response."

What his team didn't know, but knew had to exist, was the protein that could trigger the IL-1 response. Superti-Furga used all the 'omics tools in his belt to narrow down which protein it might be. First up was a proteomic screen for proteins that would bind DNA. "We had two assumptions: one was that this protein would have to be able to bind double-stranded DNA in a rather specific way, [and] the other was that the majority of proteins that are involved in these types of responses are actually themselves turned on by interferon, interferon being the first state of alarm," he says. "The idea is that there should be a protein that is turned on by interferon and at the same time be able to bind DNA."

A pulldown assay identified 100 or so proteins that bound DNA. He then crossed that dataset with one that represented the genes turned on by interferon. That ruled out all but a handful of proteins. Of course, the protein had to be cytoplasmic, and the only one remaining was AIM2. To validate AIM2 as the patrolling agent, the team used a knockdown approach. When the scientists transfected siRNAs against AIM2 into THP-1 human monocytic cells, they saw decreased AIM2 mRNA and a consistent decrease in DNA-mediated secretion of IL-1β that did not occur with any of the negative controls. "Without this protein, you don't have this response," says Superti-Furga.

Superti-Furga wasn't the only one on the hunt for AIM2, as three other groups from Worcester, Mass., Philadelphia, and Brisbane, Australia reported identifying the same protein in papers appearing at the same time in Nature and Science. While it's not surprising that viruses can elicit an IL-1 response, "it wasn't quite obvious to the community that you could take naked DNA, challenge competent macrophages, and have that by itself trigger [this] response," Superti-Furga says. Only in early 2008 did published research point to the obvious, that there must be a receptor responsible for this activity.

In future studies Superti-Furga would like to screen for more proteins that might work in complement to AIM2. He'd also like to further characterize the protein: "For example, what is the role of AIM2 in cancer? Why has it been identified as lost in melanoma? Could it be related to this pro-inflammatory function?" he wonders. His lab has already begun to screen for proteins that interact with AIM2, as it's likely that it's not acting alone, he says.