Death Comes for the Fungus: Yeast protein mimics mammalian cell suicide trigger (Apoptosis)

Abstract

For decades, yeast have taught scientists how cells live; now it seems that the microbes might also reveal how cells die. A yeast protein behaves similarly to mammalian proteins that coordinate a cell suicide mechanism, according to new work. If the protein's function is confirmed, it will help build the argument that yeast and mammalian cells can die by similar means. The study hints that yeast could reveal the evolutionary origins of this death wish. Animals use a lethal tool called apoptosis to dispose of cells that have outlived their usefulness or that pose a threat to the organism. Protein-cutting enzymes called caspases regulate the process: When cells encounter damaging agents such as hydrogen peroxide, caspases come to life and activate molecules that set apoptosis in motion. Although some results have hinted that yeast can die by a process similar to apoptosis, the fact that scientists hadn't found a functional yeast caspase left many researchers skeptical. Two years ago, researchers discovered that the genomes of many organisms, including plants and yeast, harbor genes called metacaspases that distantly resemble mammalian caspase genes, but no one knew their function. Madeo and colleagues investigated how the yeast metacaspase gene, which they named YCA1 , affected yeast vitality. They engineered yeast to produce large amounts of YCA1 protein. Then they treated cultures with hydrogen peroxide and measured the fraction of cells that could grow on a petri dish. An abnormally high percentage of modified cells could not. The dead cells showed signs of having undergone apoptosis; for instance, they contained chopped-up DNA. But cells with abundant YCA1 survived if they also lacked a protein whose mammalian counterpart lies downstream of caspases in the apoptosis pathway. In addition, whereas extra YCA1 rendered cells susceptible to hydrogen peroxide, absence of the protein hardened them against the chemical insult. The results suggest that YCA1 triggers cell death in yeast. Additional experiments revealed that the YCA1 protein performs caspaselike biochemical feats. For example, the researchers tested the ability of yeast extracts to cleave three of the proteins that mammalian caspases target. They treated cells with hydrogen peroxide, ground them up, and found that material from yeast that pumped out YCA1 cut the test molecules much faster than that from control strains. The authors conclude that YCA1 regulates yeast apoptosis by a protein-cutting activity reminiscent of that exhibited by mammalian caspases. Because the yeast gene's sequence isn't very close to that of mammalian caspases, scientists hadn't predicted such behavior. "I'm really quite surprised," says biochemist Guy Salvesen of the Burnham Institute in La Jolla, California. But to be convinced that YCA1 is a bona fide caspase, he would like to see evidence that the protein snips caspase substrates specifically and not other molecules. Other researchers still wonder whether yeast are really undergoing apoptosis. "It could be an ancient form of cell death that you probably ought to call something else," says biochemist Lisa Ellerby of the Buck Institute for Age Research in Novato, California. Even if that's true, she says, understanding cell death in yeast could reveal how apoptosis evolved. --R. John Davenport; suggested by Greg Liszt F. Madeo, E. Herker, C. Maldener, S. Wissing, S. Lächelt, M. Herlan, M. Fehr, K. Lauber, S. J. Sigrist, S. Wesselborg, K.-U. Fröhlich, A caspase-related protease regulates apoptosis in yeast. Mol. Cell 9 , 911-917 (2002). [Abstract] [Full Text]