Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies

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.
Science (Impact Factor: 33.61). 03/2010; 327(5970):1223-8. DOI: 10.1126/science.1182228
Source: PubMed


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.

    • "Sestrins also modulate mitochondrial function, probably associated with the negative control of mTOR through AMPKα1 phosphorylation and the clearance of damaged mitochondria [111] [112] [113]. Several studies have shown that protection against energeticstress and metabolic alterations associated with aging and obesity is fundamentally dependent on SESN2 and SESN3 activation [109] [112] [114]. "
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    ABSTRACT: Mitochondria are key players in the maintenance of cellular homeostasis, as they generate ATP via OXPHOS. As such, disruption in mitochondrial homeostasis is closely associated with disease states, caused by subtle alterations in the function of tissues or by major defects, particularly evident in tissues with high metabolic demands. Adaptations in mitochondrial copy number or mitochondrial mass, and also the induction of genes implicated in OXPHOS or in intermediary metabolism as well depend on the balanced contribution of both the nuclear and mitochondrial genomes. This forms a biogenesis program, controlled by several nuclear factors that act coordinately and in a categorized manner. Dynamic changes in mitochondrial regulators are associated with post-translational modifications mediated by metabolic sensors, such as SIRT1 and AMPK. Nrf2, which induces an antioxidant protective response against oxidative stress, also modulates bioenergetic function and metabolism. Additionally, the stability of mitochondrial transcripts is decreased by miRNA detected in the mitochondria, thus affecting the bioenergetic capacity of the cell. However, mitochondrial adaptation to metabolic demands is also dependent on the removal of damaged mitochondria (mitophagy) and fission/fusion events of the mitochondrial network.
    No preview · Article · May 2015 · Current Medicinal Chemistry
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    • "Nuclear translocation of FoxO has been implicated in cellular protection against OS via the transcriptional regulation of manganese superoxide dismutase (MnSOD) and catalase (Cat) gene expression (Glauser and Schelegel, 2007). FoxO can also induce transcriptional activation of sestrin (dSesn), which could lead to elevated levels of the energy sensor protein AMP-activated protein kinase (AMPK), which has an inhibitory effect on the transcription of the Drosophila homolog of the target of rapamycin (dTOR) (Lee et al., 2010). The sestrins are a family of highly conserved proteins that were originally discovered in mammals as antioxidants (Peeters et al., 2003; Budanov et al., 2004). "
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    ABSTRACT: Insect adipokinetic hormones (AKHs) are pleiotropic hormones known to play a protective role in response to oxidative stress (OS). However, the precise signaling pathways are unclear. We present evidence that AKH may primarily employ the Forkhead box class O transcription factor (FoxO) to exert this effect. The impact of knocking down AKH synthesis or its over-expression in response to OS was studied in Drosophila melanogaster. AKH knockdown (AKH-RNAi) as well as AKH overexpression (AKH-oex) was achieved using the Gal-4/UAS system and controls were w(1118) (+/+), AKH-Gal4/+, UAS-AKH/+ and UAS-AKH-RNAi/+. Exposure to 80μM hydrogen peroxide (HP) revealed that AKH-RNAi flies showed significantly higher mortality than AKH-oex or the respective control lines. This susceptibility was evidenced by significantly enhanced levels of protein carbonyls - a biomarker of OS, in AKH-RNAi flies compared to controls and AKH-oex flies. Interestingly, AKH-oex flies had the least amount of protein carbonyls. AKH-RNAi flies had significantly less dFoxO transcript and translated protein compared to control and AKH-oex flies in un-challenged condition as well as when challenged with HP. Sestrin - a major antioxidant defense protein and one of the targets of dFoxO - was also significantly down-regulated (both at mRNA and protein level) in AKH-RNAi flies (both unchallenged and challenged with HP) compared to control flies and flies with over-expressed AKH. These findings imply that dFoxO may act downstream of AKH as a transcription factor to mediate response to OS in D. melanogaster. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology
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    • "Indeed, while dSestrin gain of function inhibits mTORC1 signaling and cell growth in Drosophila, dSestrin deficiency results in an age-dependent metabolic syndrome caused by mTORC1 hyperactivation (Lee et al., 2010). Likewise, Sestrin2- deficient mice fail to inactivate mTORC1 in the liver during fasting (Bae et al., 2013), and spontaneously elevated mTORC1 signaling is observed in mice devoid of both Sestrin2 and Ses- trin3 (Lee et al., 2012). "
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    ABSTRACT: Mechanistic target of rapamycin complex 1 (mTORC1) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. Here, we show that Sestrins bind to the heterodimeric RagA/B-RagC/D GTPases, and function as guanine nucleotide dissociation inhibitors (GDIs) for RagA/B. Sestrin overexpression inhibits amino-acid-induced Rag guanine nucleotide exchange and mTORC1 translocation to the lysosome. Mutation of the conserved GDI motif creates a dominant-negative form of Sestrin that renders mTORC1 activation insensitive to amino acid deprivation, whereas a cell-permeable peptide containing the GDI motif inhibits mTORC1 signaling. Mice deficient in all Sestrins exhibit reduced postnatal survival associated with defective mTORC1 inactivation in multiple organs during neonatal fasting. These findings reveal a nonredundant mechanism by which the Sestrin family of GDIs regulates the nutrient-sensing Rag GTPases to control mTORC1 signaling.
    Full-text · Article · Sep 2014 · Cell
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