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Title: Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies.

Authors: Lee, Jun Hee; Budanov, Andrei V; Park, Eek Joong; Birse, Ryan; Kim, Teddy E; Perkins, Guy A; Ocorr, Karen; Ellisman, Mark H; Bodmer, Rolf; Bier, Ethan; Karin, Michael

Published In Science, (2010 Mar 05)

Abstract: Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.

PubMed ID: 20203043 Exiting the NIEHS site

MeSH Terms: AMP-Activated Protein Kinases/metabolism; Aging*; Amino Acid Sequence; Animals; Autophagy; Cell Size; Drosophila Proteins/antagonists & inhibitors; Drosophila Proteins/chemistry; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila Proteins/physiology*; Drosophila melanogaster/cytology; Drosophila melanogaster/growth & development; Drosophila melanogaster/metabolism; Drosophila melanogaster/physiology*; Fat Body/metabolism; Feedback, Physiological; Forkhead Transcription Factors/metabolism; Gene Expression Regulation; Heart/physiology; Heat-Shock Proteins/chemistry; Heat-Shock Proteins/genetics; Heat-Shock Proteins/physiology*; JNK Mitogen-Activated Protein Kinases/metabolism; Mitochondria, Muscle/physiology; Mitochondria, Muscle/ultrastructure; Models, Animal; Molecular Sequence Data; Muscles/physiology; Oxidative Stress; Protein Kinases/metabolism*; Reactive Oxygen Species/metabolism; Signal Transduction; TOR Serine-Threonine Kinases; Transcription, Genetic; Triglycerides/metabolism; Wings, Animal/cytology; Wings, Animal/growth & development; Wings, Animal/metabolism

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