'Reaper' protein strikes at mitochondria to kill cells

October 20, 2010 in Biology / Cell & Microbiology
The results could be plainly seen in the how the eyes developed. Here is a normal eye (left) beside one that's almost completely destroyed by apoptosis (right).


In experiments published last month in the Journal of Cell Biology, researchers led by postdoctoral associate Cristinel Sandu in Hermann Steller’s Strang Laboratory of Apoptosis and Cancer Biology drilled down on a protein aptly named Reaper, which was first described in a 1994 paper by Steller in Science. Under the right conditions, Reaper interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent the cell from irrevocably initiating its autodestruct sequence. By inhibiting these inhibitors, Reaper essentially takes the brakes off the process of apoptosis, pronouncing a cell’s death sentence. Other molecules called caspases then carry that sentence out.

“Like the grim reaper, Reaper is an announcer of death, but not the executioner,” says Steller, who is also a Howard Hughes Medical Institute investigator. “It’s like the key that starts the engine.”

Reaper and the other Drosophila IAP antagonists Hid and Grim are known to trigger apoptosis in flies, and related proteins serve a similar function in humans and other mammals. But exactly how and where Reaper initiates apoptosis has not been well understood. Sandu and colleagues bred genetically modified strains of flies that expressed variations on the Reaper protein specifically in flies’ eyes. This allowed them to assess the contribution of individual protein motifs to Reaper’s apoptosis inducing powers, and what they found was that a particular helical domain was crucial for the formation of Reaper complexes, and could be modified to be even more powerful than the regular protein. The more deadly Reaper variants were obvious by the damage caused to the flies’ eyes.


“So now we have Hid and Reaper working very closely together,” Sandu says. “And the localization to the mitochondria is crucial to the initiation of apoptosis.” Drugs that mimic a small part of the function of Reaper are already in clinical trials. The discovery of a way to make Reaper a much better killer, namely by targeting it directly to the mitochondria, provides new avenues to explore for improving cancer therapies. “Adding this element that takes Reaper directly to the mitochondria is not something people would have thought of before this,” Steller says.

More information: Journal of Cell Biology 190: 1039–1052 (September 20, 2010) Drosophila IAP antagonists form multimeric complexes to promote cell death Cristinel Sandu, et al.

Provided by Rockefeller University

"'Reaper' protein strikes at mitochondria to kill cells" October 20, 2010 http://phys.org/news/2010-10-reaper-protein-mitochondria-cells.html