title: Asymmetric Inheritance of Aggregated Proteins and Age Reset in Yeast Are Regulated by Vac17-Dependent Vacuolar Functions.
abstract: 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.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, S-413 90 Göteborg, Sweden.
authors.forename: Sandra Malmgren
authors.initials: SM
authors.lastname: Hill
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, S-413 90 Göteborg, Sweden.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Grönvall
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Spikings-Nordby
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, S-413 90 Göteborg, Sweden.
authors.forename: Per O
authors.initials: PO
authors.lastname: Widlund
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Triana
authors.initials: T
authors.lastname: Amen
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Jörhov
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, S-413 90 Göteborg, Sweden.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Josefson
authors.affiliation: Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kaganovich
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden. Electronic address: beidong.liu@cmb.gu.se.
authors.forename: Beidong
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Medicinaregatan 9C, S-413 90 Göteborg, Sweden; Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 7A, S-413 90 Göteborg, Sweden. Electronic address: thomas.nystrom@cmb.gu.se.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
mesh_terms: D034281:Dynamins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D066329:Protein Aggregates / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism* / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism / Q000502:physiology; D014617:Vacuoles / Q000378:metabolism* / Q000502:physiology*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D011956:Receptors, Cell Surface; D029701:Saccharomyces cerevisiae Proteins; C472499:VAC17 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D034281:Dynamins