Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1


Advanced cellular age is associated with decreased efficiency of the proteostasis network. The proteasome, a protease in the cytoplasm and nuclei of eukaryotic cells, is an important component of this network. Recent studies demonstrate that increased proteasome capacity has a positive impact on longevity. The underlying mechanisms, however, have not been fully identified. Here we report that proteasomes are involved in regulating the AMP-activated kinase (AMPK) pathway and thus participate in correct metabolic adaptation. We find that Mig1, a transcriptional repressor downstream of yeast AMPK, Snf1, is a proteasome target and a negative regulator of lifespan. Increased proteasome activity results in enhanced turnover and incorrect localization of Mig1. The reduced Mig1 levels result in the induction of respiration and upregulation of the oxidative stress response. Premature Mig1 inactivation is also observed in two additional long-lived strains that overexpress SIR2 or are deleted for HXK2 and lifespan extension in both strains requires correct proteasome function. Our results uncover an interconnected network comprised of the proteasome, Sir2 and AMPK/Hxk2 signaling that impacts longevity through regulation of Mig1 and modulates respiratory metabolism. Mechanistic information on the cross-communication between these pathways is expected to facilitate the identification of novel pro-aging interventions.


Vyšlo v časopise: Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004968
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004968

Souhrn

Advanced cellular age is associated with decreased efficiency of the proteostasis network. The proteasome, a protease in the cytoplasm and nuclei of eukaryotic cells, is an important component of this network. Recent studies demonstrate that increased proteasome capacity has a positive impact on longevity. The underlying mechanisms, however, have not been fully identified. Here we report that proteasomes are involved in regulating the AMP-activated kinase (AMPK) pathway and thus participate in correct metabolic adaptation. We find that Mig1, a transcriptional repressor downstream of yeast AMPK, Snf1, is a proteasome target and a negative regulator of lifespan. Increased proteasome activity results in enhanced turnover and incorrect localization of Mig1. The reduced Mig1 levels result in the induction of respiration and upregulation of the oxidative stress response. Premature Mig1 inactivation is also observed in two additional long-lived strains that overexpress SIR2 or are deleted for HXK2 and lifespan extension in both strains requires correct proteasome function. Our results uncover an interconnected network comprised of the proteasome, Sir2 and AMPK/Hxk2 signaling that impacts longevity through regulation of Mig1 and modulates respiratory metabolism. Mechanistic information on the cross-communication between these pathways is expected to facilitate the identification of novel pro-aging interventions.


Zdroje

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