Asymmetric Inheritance of Aggregated Proteins and Age Reset in Yeast Are Regulated by Vac17-Dependent Vacuolar Functions

Age can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae, we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan. The link between damage asymmetry and vesicle trafficking can be explained by a direct interaction between aggregates and vesicles. We also show that the protein disaggregase Hsp104 interacts physically with endocytic vesicle-associated proteins, such as the dynamin-like protein, Vps1, which was also shown to be required for Vac17-dependent sequestration of protein aggregates. These data demonstrate that two physiognomies of aging—reduced endocytosis and protein aggregation—are interconnected and regulated by Vac17. [Display omitted] •Vesicle trafficking and fusion control asymmetric inheritance of aggregated proteins•Vac17 increases vacuole-proximal fusion of aggregated proteins and extends lifespan•Hsp104 interacts physically with endomembrane trafficking components, including Vps1•Quality control by Vac17 requires Myo2 binding, membrane tethering, and Vps1 Cellular rejuvenation is enabled by asymmetrical inheritance of damaged proteins. Using a genome-wide imaging screen to identify asymmetry-generating genes, Hill et al. demonstrate a role for vesicle trafficking, membrane fusion, and the myosin-dependent adaptor protein Vac17 in the asymmetric inheritance of misfolded proteins and consequently in the regulation of lifespan.