Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies.
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.
Lee
Jun Hee
JH
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093-0723, USA.
Budanov
Andrei V
AV
Park
Eek Joong
EJ
Birse
Ryan
R
Kim
Teddy E
TE
Perkins
Guy A
GA
Ocorr
Karen
K
Ellisman
Mark H
MH
Bodmer
Rolf
R
Bier
Ethan
E
Karin
Michael
M
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D048429:Cell Size; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D005216:Fat Body / Q000378:metabolism; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000502:physiology / Q000648:ultrastructure; D023421:Models, Animal; D008969:Molecular Sequence Data; D009132:Muscles / Q000502:physiology; D018384:Oxidative Stress; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; D014280:Triglycerides; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases