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Apoptotic cells let down their guard

Glutathionylated proteins (green) show up in cells after stimulation of Fas.

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.

References

Anathy, V., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200807019.[Abstract/Free Full Text]

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Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas

Vikas Anathy, Scott W. Aesif, Amy S. Guala, Marije Havermans, Niki L. Reynaert, Ye-Shih Ho, Ralph C. Budd, and Yvonne M.W. Janssen-Heininger
J. Cell Biol. 2009 184: 241-252. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 665K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Leslie, M. Search for Related Content PubMed Articles by Leslie, M. Related Collections Related Article Social Bookmarking                            What's this?