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Aggregation of the Whi3 protein, not loss of heterochromatin, causes sterility in old yeast cells

Protein aggregation–mediated aging in yeast Old age in yeast cells results in insensitivity to mating pheromone. Reduced activity of the histone deactylase Sir2 and consequent alteration of chromatin at mating loci have been implicated in the decreased sensitivity of old cells. However, Schlissel et al. found a different mechanism in the yeast strains that they studied (see the Perspective by Gitler and Jarosz). Proper response to mating pheromone requires arrest of the cell cycle mediated by an RNA-binding protein, Whi3. If aggregation of Whi3 in old cells was inhibited by deletion of a glutamine-rich region that promotes aggregation, loss of sensitivity to mating pheromone was partially prevented, and replicative life span was slightly increased. Science, this issue p. 1184; see also p. 1126 Sterility of old yeast cells is caused by protein aggregation. In yeast, heterochromatin silencing is reported to decline in aging mother cells, causing sterility in old cells. This process is thought to reflect a decrease in the activity of the NAD+ (oxidized nicotinamide adenine dinucleotide)–dependent deacetylase Sir2. We tested whether Sir2 becomes nonfunctional gradually or precipitously during aging. Unexpectedly, silencing of the heterochromatic HML and HMR loci was not lost during aging. Old cells could initiate a mating response; however, they were less sensitive to mating pheromone than were young cells because of age-dependent aggregation of Whi3, an RNA-binding protein controlling S-phase entry. Removing the polyglutamine domain of Whi3 restored the pheromone sensitivity of old cells. We propose that aging phenotypes previously attributed to loss of heterochromatin silencing are instead caused by aggregation of the Whi3 cell cycle regulator.