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Confocal microscopy images show a cell stained with an antibody for the MAVS protein (left, green) and a mitochondria-specific dye (center, red). An overlay of the green and red images (right) indicates the mitochondrial localization of MAVS.
The group reported their findings in the September 9, 2005, issue of Cell; soon after, Science STKE named the discovery of MAVS one of the "signaling breakthroughs" of the year. Eric A. Shoubridge, a human geneticist and HHMI international research scholar at McGill University, in Montreal, Canada, says, "Chen's work is pretty exciting stuff. Random bits of information had suggested that mitochondria might be involved in signaling and the immune system, but this work is the clearest evidence yet—it's very convincing."
Once he discovered MAVS, Chen investigated whether some viruses could specifically target the protein to cripple a host's defenses. "After we found MAVS, we suspected maybe it was the long-sought-after target for the hepatitis C virus," he explains. Of the 170 million people in the world with hepatitis C, about 80 percent have persistent, chronic infections; their interferon production is suppressed. Sure enough, Chen's group discovered that the hepatitis C virus, using an enzyme called a protease, can clip MAVS off the mitochondrial membrane, effectively breaking the signaling pathway that triggers interferon production. The group reported these findings in the December 6, 2005, issue of the Proceedings of the National Academy of Sciences.
Chen's team further observed that a change in just one letter of the MAVS genetic code—the kind of simple mutation that typically distinguishes the DNA of one individual from that of another—protects it from being clipped by the viral protease. This observation may explain why some people are better than others at fighting off hepatitis C infection and suggests an important target for drug treatments. "If we could come up with an inhibitor of the viral protease, we could prevent viral replication and also restore [interferon production in] the host immune system—like killing two birds with one stone," says Chen.
A lot more remains to be learned about MAVS. Chen's group is exploring whether other viruses also target MAVS, whether other mechanisms can be used to cripple it, and whether MAVS serves any other functions in the cell. For instance, does MAVS ever talk to neighboring membrane proteins and tell them to trigger cell suicide? Theoretically, it would make sense for cells to use suicide as an additional antiviral strategy; plant cells are known to use it to limit the spread of infection for the benefit of the whole organism. "Maybe if a mammalian cell can't produce enough interferons, then it will need to die," Chen theorizes. However, any link between MAVS and cell suicide is still speculative, he says.
In most tissues, mitochondria consume 90 percent of the oxygen that enters the body. So it makes sense that mitochondria would function as oxygen sensors as well. M. Celeste Simon, an HHMI investigator at the University of Pennsylvania School of Medicine, decided to explore this idea in 1997. "Understanding how oxygen levels are sensed and adapted to is fundamentally important to dealing with pretty much all of the major diseases that we encounter—atherosclerosis, autoimmune disease, stroke, and cancer," she says. For instance, solid tumors begin to grow outside the body's circulatory system, where oxygen levels are low, and they do so by turning on signals that tell tissues to sprout new blood vessels. Understanding how to disrupt this signaling might lead to new cancer treatments. Normal adult tissues, such as kidneys, can also experience low oxygen because of poor circulation and other dysfunctions. In that case, if doctors could enhance the signaling process, they might be able to promote blood vessel development and restore an organ's function.
Image: Courtesy of Rashu B. Seth and Zhijian 'James' Chen