title: Proteasomes, Sir2, and Hxk2 form an interconnected aging network that impinges on the AMPK/Snf1-regulated transcriptional repressor Mig1.
abstract: Elevated proteasome activity extends lifespan in model organisms such as yeast, worms and flies. This pro-longevity effect might be mediated by improved protein homeostasis, as this protease is an integral module of the protein homeostasis network. Proteasomes also regulate cellular processes through temporal and spatial degradation of signaling pathway components. Here we demonstrate that the regulatory function of the proteasome plays an essential role in aging cells and that the beneficial impact of elevated proteasome capacity on lifespan partially originates from deregulation of the AMPK signaling pathway. Proteasome-mediated lifespan extension activity was carbon-source dependent and cells with enhancement proteasome function exhibited increased respiratory activity and oxidative stress response. These findings suggested that the pro-aging impact of proteasome upregulation might be related to changes in the metabolic state through a premature induction of respiration. Deletion of yeast AMPK, SNF1, or its activator SNF4 abrogated proteasome-mediated lifespan extension, supporting this hypothesis as the AMPK pathway regulates metabolism. We found that the premature induction of respiration in cells with increased proteasome activity originates from enhanced turnover of Mig1, an AMPK/Snf1 regulated transcriptional repressor that prevents the induction of genes required for respiration. Increasing proteasome activity also resulted in partial relocation of Mig1 from the nucleus to the mitochondria. Collectively, the results argue for a model in which elevated proteasome activity leads to the uncoupling of Snf1-mediated Mig1 regulation, resulting in a premature activation of respiration and thus the induction of a mitohormetic response, beneficial to lifespan. In addition, we observed incorrect Mig1 localization in two other long-lived yeast aging models: cells that overexpress SIR2 or deleted for the Mig1-regulator HXK2. Finally, compromised proteasome function blocks lifespan extension in both strains. Thus, our findings suggest that proteasomes, Sir2, Snf1 and Hxk2 form an interconnected aging network that controls metabolism through coordinated regulation of Mig1.
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Yanhua
authors: Y
authors: Yao
authors: Buck Institute, Novato, California, United States of America.
authors: Scott
authors: S
authors: Tsuchiyama
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Ciyu
authors: C
authors: Yang
authors: LCABIE UMR5254, Technopôle Hélioparc Pau Pyrénées, Pau, France.
authors: Anne Laure
authors: AL
authors: Bulteau
authors: Buck Institute, Novato, California, United States of America.
authors: Chong
authors: C
authors: He
authors: Buck Institute, Novato, California, United States of America.
authors: Brett
authors: B
authors: Robison
authors: Buck Institute, Novato, California, United States of America.
authors: Mitsuhiro
authors: M
authors: Tsuchiya
authors: Buck Institute, Novato, California, United States of America.
authors: Delana
authors: D
authors: Miller
authors: Buck Institute, Novato, California, United States of America.
authors: Valeria
authors: V
authors: Briones
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Krisztina
authors: K
authors: Tar
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Anahi
authors: A
authors: Potrero
authors: Laboratoire de Biologie Cellulaire du Vieillissement, UR4-IFR83, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors: Bertrand
authors: B
authors: Friguet
authors: Buck Institute, Novato, California, United States of America.
authors: Brian K
authors: BK
authors: Kennedy
authors: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, New York, United States of America.
authors: Marion
authors: M
authors: Schmidt
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C085976:MIG1 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C071570:SNF1-related protein kinases; C490214:HXK2 protein, S cerevisiae; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
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