Reactive oxygen species (ROS) help push suicidal cells over the edge, but the mechanism behind this has been murky. Now, Anathy et al. reveal the counterintuitive process through which ROS promote apoptosis.
The Fas receptor is a cellular grim reaper. Stimulation of the receptor sets off a molecular chain of events, including activation of caspases, which eventually triggers apoptosis. ROS seem to nudge the process along. Although ROS are best known for their destructiveness, they also perform many other cellular functions, including relaying messages. Anathy et al. wanted to nail down how ROS influence the Fas pathway.
The obvious mechanism—that Fas activation triggers a surge of ROS, amplifying the death pathway—appears to be wrong, the researchers found. Instead, upon stimulation of the receptor, the same caspases that spur the cell death program also drive the destruction of the antioxidant protein glutaredoxin 1.
The decline in glutaredoxin 1 makes an impact. High levels of ROS can trigger glutathionylation—the addition of a glutathione molecule to cysteine amino acids in a protein. The amount of glutathionylation climbed after Fas stimulation—a rise the researchers could prevent by cranking up glutaredoxin 1 production.
So ROS's role in the cell's demise is to spur glutathionylation. But rather than boosting ROS levels to ramp up glutathionylation, cells achieve the same effect by degrading glutaredoxin 1 and dialing down their defenses against oxidation. How glutathionylation promotes cellular suicide isn't clear. But Fas itself is glutathionylated, and the altered receptors bunch up and slip into lipid rafts in the cell membrane, possibly strengthening signaling through the Fas pathway.