A cell must act fast to ward off a virus effectively: It must launch an immune response even if it detects only a few viral particles. Howard Hughes Medical Institute scientists have found that an immune defense protein that behaves like a prion makes this rapid response possible. It’s a rare example of a beneficial effect of prions, which are better known for aggressively recruiting other similar proteins to form large, tangled clumps inside brain cells.
A typical prion is a misfolded version of a particular protein, and just one prion in a mix of normal proteins can coax all the proteins to misfold. The misfolded proteins clump together and interfere with normal cell function. Introducing a prion to a cell is like knocking over the first tile in a long line of dominoes: Each tile knocks over the next in line. When this happens to proteins in the brain, it causes diseases such as bovine spongiform encephalopathy (“mad cow disease”) or Creutzfeldt-Jakob disease.
HHMI investigator Zhijian J. Chen of the University of Texas Southwestern Medical Center -- whose team discovered the prion-like component of cell’s antiviral response and described it in the July 21, 2011, issue of the journal Cell -- didn’t set out to study prions. Chen is broadly interested in how viruses trigger host immune responses. He had previously discovered some of the molecules cells use to detect and fight off viruses, including a protein called MAVS (mitochondrial antiviral signaling). MAVS is found on the membranes of mitochondria—energy-producing organelles in the cell—but until now, it hadn’t been clear how MAVS works.
To study the role of MAVS in the antiviral immune response, Chen and his colleagues created a setup that allowed them to study the whole immune response outside of a cell. “We reconstituted this whole pathway in a test tube,” says Chen. “We broke cells open, mixed different parts and then added viral RNA to mimic the immune response.”
The effect on MAVS was drastic, and immediate. “When we infected cells with a virus or added the viral RNA to our test tube mix, MAVS started to form very large aggregates on the mitochondrial surface.”
The researchers isolated the MAVS aggregates from the cells and found hundreds of MAVS molecules in each clump. Moreover, chemicals that normally break up protein aggregates did little to separate the MAVS from each other.
“This reminded us of prions,” says Chen. “But the most important feature of prions is that they can cause the native protein to also form aggregates.”
So Chen’s team added preformed fiber-like aggregates of MAVS to mitochondria isolated from human cells that hadn’t been exposed to a virus. Within minutes, every MAVS on the mitochondria had joined together into aggregate forms. The response mirrored what scientists see when they add misfolded prions to a sample of normal proteins.
To study whether the prion-like aggregation is important to the immune response, the scientists blocked MAVS molecules from binding to each other. This time, when they added viruses to the cells, no immune response was launched. In another experiment, they added a MAVS aggregate to their test-tube immune system. Even without the addition of a virus, the activated MAVS was enough to launch an immune response. The aggregation of the proteins, the researchers concluded, was both required for the antiviral immune response, and sufficient to cause the response.
When misfolded proteins rapidly overwhelm a cell – as they do in prion diseases –the result is catastrophic. But the domino effect of MAVS allows cells to fight disease. “This is a dramatic example of these prion-like mechanisms being very beneficial to the host,” says Chen. “In this case, it allows a highly sensitive and robust immune response to viruses.”
The prion-like mechanism of MAVS allows the cell to launch a full-blown antiviral response even if it senses only a few copies of a virus, Chen says. If one or two MAVS proteins are activated, they might not be able to trigger a strong enough immune response on their own. But if they quickly activate all their neighbors to the defense form of the protein, the response will be much larger.
There are still many more details of the pathway to work out. How does MAVS transition from its normal conformation to the conformation that forms aggregates? What are the conformations of inactive and active MAVS? How exactly does the MAVS aggregation cause the next step in the immune response? And lastly, do these aggregates ever come apart or go away? What happens when the antiviral response is over?
Also, Chen adds, “It will be really interesting to see, as we go forward, if there are other occurrences in mammalian cells of this type of beneficial prion mechanism.”