InteractiveFly: GeneBrief

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Gene name - Sestrin

Synonyms - CG11299

Cytological map position - 59F6-59F7

Function - signaling

Keywords - negative feedback regulator of TOR pathway, regulation of autophagy

Symbol - Sesn

FlyBase ID: FBgn0034897

Genetic map position - 2R:19,601,425..19,620,706 [+]

Classification - PA26 super family

Cellular location - cytoplasmic

NCBI link: EntrezGene

Sestrin orthologs: Biolitmine
Recent literature
Cobb, T., Damschroder, D. and Wessells, R. (2021). Sestrin regulates acute chill coma recovery in Drosophila melanogaster. Insect Biochem Mol Biol: 103548. PubMed ID: 33549817
When chill-susceptible insects are exposed to low temperatures they enter a temporary state of paralysis referred to as a chill coma. The most well-studied physiological mechanism of chill coma onset and recovery involves regulation of ion homeostasis. Previous studies show that changes in metabolism may also underlie the ability to recovery quickly, but the roles of genes that regulate metabolic homeostasis in chill coma recovery time (CCRT) are not well understood. This study investigated the roles of Sestrin and Spargel (Drosophila homolog of PGC-1α), which are involved in metabolic homeostasis and substrate oxidation, on CCRT in Drosophila melanogaster. sestrin and spargel mutants have impaired CCRT. sestrin is required in the muscle and nervous system tissue for normal CCRT and spargel is required in muscle and adipose. On the basis that exercise induces sestrin and spargel, the interaction of cold and exercise was tested. Pre-treatment with one of these stressors does not consistently confer acute protection against the other. It is concluded that Sestrin and Spargel are important in the chill coma response, independent of their role in exercise.

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). 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 (see AMP-activated protein kinase) 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, 2010).

Target of rapamycin (TOR) is a key protein kinase that regulates cell growth and metabolism to maintain cellular and organismal homeostasis. Insulin and insulin-like growth factors are major TOR activators that operate through phosphoinositide 3-kinase (PI3K) and the protein kinase AKT. Conversely, adenosine monophosphate-activated protein kinase (AMPK), which is activated upon energy depletion, caloric restriction (CR), or genotoxic damage, is a stress-responsive inhibitor of TOR activation. TOR stimulates cell growth and anabolism by increasing protein and lipid synthesis through p70 S6 kinase (S6K), eukaryotic translation initiation factor 4E-binding protein (4E-BP), and sterol response element binding protein (SREBP) and by decreasing autophagic catabolism through phosphorylation-mediated inhibition of ATG1 protein kinase. Persistent TOR activation is associated with diverse pathologies such as cancer, diminished cardiac performance, and obesity-associated metabolic diseases. Conversely, inhibition of TOR prolongs life span and increases quality of life by reducing the incidence of age-related pathologies. The antiaging effects of CR could be due to inhibition of TOR (Lee, 2010 and references therein).

Sestrins (Sesns) are highly conserved proteins that accumulate in cells exposed to stress, lack obvious domain signatures, and have poorly defined physiological functions (Budanov, 2002; Velasco-Miguel, 1999). Mammals express three Sesns, whereas Drosophila melanogaster and Caenorhabditis elegans have single orthologs. In vitro, Sesns exhibit oxidoreductase activity and may function as antioxidants (Budanov, 2004). Independently of their redox activity, Sesns lead to AMPK-dependent inhibition of TOR signaling and link genotoxic stress to TOR regulation (Budanov, 2008). However, Sesns are also widely expressed in the absence of exogenous stress, and in Drosophila, expression of Drosophila sestrin (dSesn) is increased upon maturation and aging. Given the redundancy between mammalian Sesns, the importance of Sesns as regulators of TOR function was tested in Drosophila. Both gain- and loss-of-function dSesn mutants were created. Analysis of these mutants revealed that dSesn is an important negative feedback regulator of TOR whose loss results in various TOR-dependent, age-related pathologies (Lee, 2010).

Persistent TOR activation in wing discs by a constitutively active form of the insulin receptor (InRCA) resulted in prominent dSesn protein accumulation, which is not seen in a dSesn-null larvae. InRCA also induced accumulation of dSesn RNA, indicating that dSesn accumulation is due to increased transcription or mRNA stabilization. Since dSesn accumulation was restricted to cells in which TOR was activated, the response is likely to be cell autonomous. dSesn was also induced when TOR was chronically activated by overexpression of the small guanine triphosphatase Rheb, clonal loss of phosphatase and tensin homolog (PTEN), or tuberous sclerosis complex 1 (TSC1). Dominant-negative PI3K (PI3KDN) or TOR (TORDN) inhibited dSesn accumulation caused by overexpression of InRCA, but inactive ribosomal S6 protein kinase (S6K, S6KDN) and hyperactive 4E-BP (4E-BPCA), two downstream TOR effectors, did not. Furthermore, dorsal-specific expression of activated S6KCA or loss of 4E-BP activity failed to induce dSesn expression, indicating that TOR regulates expression of dSesn through different effector(s) (Lee, 2010).

In mammals, transcription of Sesn genes is increased in cells exposed to oxidative stress (Budanov, 2004), and reactive oxygen species (ROS) accumulation, detected by oxidation of dihydroethidium (DHE), was observed in the same region of the imaginal discs in which InRCA or Rheb were expressed. InRCA-induced accumulation of ROS was blocked by coexpression of either PI3KDN or TORDN, but not S6KDN or 4E-BPCA, revealing TOR’s role in ROS accumulation. Wing-disc clones in which TOR was activated by loss of TSC1 also exhibited ROS accumulation, confirming that TOR-dependent ROS accumulation is cell-autonomous. Expression of the ROS scavengers catalase or peroxiredoxin inhibited InRCA-induced accumulation of dSesn. Feeding animals with vitamin E, an antioxidant, also prevented dSesn induction caused by TSC1 loss (Lee, 2010).

Forkhead box O (FoxO) and p53 are ROS-activated transcription factors that control mammalian Sesn genes (Budanov, 2002; Velasco-Miguel, 1999; Budanov, 2004; Budanov, 2008; Greer, 2005). The dSesn locus contains eight perfect FoxO-response elements, a frequency 25 times higher than that expected on the basis of random distribution. Overexpressed FoxO or p53 could both increase expression of the dSesn gene. However, InRCA caused accumulation of dSesn in a p53-null background, but not in a FoxO-null background, indicating that TOR-activated FoxO is likely to be the regulator of dSesn gene transcription. Accumulation of dSesn in response to Rheb overexpression was also FoxO-dependent (Lee, 2010).

In dorsal wing disc cells, where ROS accumulated in response to InRCA, c-Jun N-terminal kinase (JNK), a protein kinase that phosphorylates FoxO, was also activated. JNK activation was diminished in cells overexpressing catalase, suggesting that it depends on TOR-induced accumulation of ROS. Mitogen-activated protein kinase kinase 7-mediated activation of JNK also resulted in accumulation of dSesn, as did overexpression of mammalian STE20-like kinase 1 (MST1), another protein kinase that phosphorylates FoxO. However, only JNKDN (but not Mst1DN) inhibited InRCA-mediated accumulation of dSesn. Collectively, these data suggest that dSesn transcription is increased upon chronic TOR activation through ROS-dependent activation of JNK and FoxO (Lee, 2010).

To determine effects of dSesn on cell growth, a major function of TOR, dSesn was overexpressed in dorsal wings. This resulted in a dose-dependent phenotype in which the wing bends upward, indicating suppressed dorsal tissue growth. A dSesnC86S variant, in which the cysteine required for oxidoreductase activity was mutated (C86S, Cys86->Ser86) (Budanov, 2004), still conferred this phenotype when expressed in amounts similar to those of wild-type dSesn (dSesnWT). Cell number and size were measured in a dorsal wing region defined by the L3, L4, C1, and C2 veins. Although the size of this area was significantly reduced by dSesn expression, the cell number remained unchanged, showing that decreased cell size can account for dSesn suppression of tissue growth. Overexpression of dSesn also reduced cell size in larval wing discs and adult eyes. Thus, dSesn inhibits cell growth without affecting cell proliferation and does so independently of its redox activity (Lee, 2010).

When dSesn was expressed with InRCA or Rheb, it suppressed the hyperplastic phenotypes caused by these TOR activators. Both eye and individual ommatidia sizes were significantly reduced. dSesn also inhibited InRCA- or Rheb-induced phosphorylation of TOR targets S6K and 4E-BP. In mammalian cells, dSesn enhanced AMPK-induced phosphorylation of TSC2 and inhibited S6K activity through TSC2, just as mSesn2 does (Budanov, 2008). In Drosophila wings, dSesn-induced growth suppression was attenuated by reduced gene dosage of TSC1, TSC2, or AMPK, although reduced dosage of these genes alone did not affect normal growth. Expression of mSesn1/2 in flies also reduced normal and InRCA-induced hyperplastic growth (Lee, 2010).

Expression of InR, constitutively active PI3K (PI3KCA), AKT, or S6KCA in dorsal cells of the wing caused an overgrowth phenotype in which the wing bends downward. dSesn expression reversed this effect of overexpressed InR, PI3KCA, and AKT, but not that of S6KCA, suggesting that dSesn inhibits TOR downstream of AKT. Conversely, dorsal wing-specific expression of PTEN and InRDN, PI3KDN, or S6KDN caused wings to bend upward, and this effect was enhanced by dSesn (Lee, 2010).

Although dSesn-null flies did not exhibit developmental abnormalities, the growth-promoting effect of overexpressed InR or AKT was enhanced in dSesn-null background, suggesting that endogenous dSesn restricts TOR activation and its growth-promoting effect. Loss of dSesn, however, did not enhance S6K-stimulated cell growth or decrease growth suppression by overexpressed InRDN or S6KDN. These findings indicate that Sesn is an evolutionarily conserved inhibitor of TOR signaling that acts via the AMPK-TSC2 axis (Lee, 2010).

Fat bodies from dSesn-null third-instar larvae contained more lipids than did those of WT animals. dSesn-null adults also contained more triglycerides, which were decreased after ectopic expression of dSesnWT or dSesnCS. Thus, the TOR-inhibitory function of dSesn, rather than its antioxidant activity, appears to affect metabolic control. Congruently, dSesn-null fat bodies showed decreased AMPK and increased TOR activities. Pharmacological manipulation strengthened this conclusion; feeding dSesn-null mutants with AMPK-activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) or metformin, or the TOR-inhibitor rapamycin reduced triglyceride accumulation (Lee, 2010).

Expression of the gene-encoding transcription factor dSREBP and its targets, which encode fatty acyl coenzyme A (CoA) synthetase, fatty acid synthase, acetyl CoA carboxylase, and acetyl CoA synthetase, was significantly increased (20 to 70%) in dSesn-null mutants. However, the peroxisome proliferator-activated receptor γ coactivator 1 (dPGC-1) gene and some lipolytic genes showed decreased expression. This is consistent with reports that dSREBP and dPGC-1 (spargel; CG9809)are inversely regulated by TOR and AMPK to properly control lipid metabolism (Lee, 2010).

Age-related decline in heart performance is another phenotype associated with TOR hyperactivity in insects and mammals. In WT flies, the heart beats in a highly regular manner, but in dSesn-null mutants, heart function was compromised, as manifested by arrhythmia and decreased heart rate. Slowing of heart rate reflected expansion of the diastolic period, as observed in aged or TOR-activated flies. These defects were largely prevented by feeding flies AICAR or rapamycin, indicating that they are caused by low activity of AMPK or high TOR activity. Vitamin E feeding or catalase expression suppressed the arrhythmia caused by loss of dSesn, but not the decrease in heart rate, suggesting that TOR-induced oxidative stress contributes to the arrhythmic phenotype. Analysis of F-actin revealed structural disorganization of myofibrils in dSesn-null hearts, suggesting that cardiac muscle degeneration may cause some of the functional defects in dSesn-null hearts. Reflecting this structural abnormality, dSesn-null hearts were dilated during both the diastolic and systolic phases, and this was prevented by AICAR or rapamycin (Lee, 2010).

Heart-specific depletion of dSesn caused cardiac malfunction similar to that seen in dSesn-null mutants. Heart-specific depletion of AMPK also caused cardiac malfunction, but this was not alleviated by AICAR administration, supporting the notion that dSesn maintains normal heart physiology through AMPK activation (Lee, 2010).

dSesn mRNA and protein are abundant in the adult thorax, which is mostly composed of Mesoderm. mSesn1 is also highly expressed in skeletal muscle (Velasco-Miguel, 1999). Therefore, whether dSesn has a role in maintaining muscle homeostasis was tested. 20-day-old dSesn-null flies showed degeneration of thoracic muscles with loss of sarcomeric structure, including discontinued Z discs, disappearance of M bands, scrambled actomyosin arrays, and diffused sarcomere boundaries. Such defects are only partially observed in very old WT flies (~90 days) and were not found in young (5-day-old) dSesn-null muscles. Thus, the dSesn-null skeletal muscle appears to undergo accelerated age-related degeneration (Lee, 2010).

Despite its normal appearance, muscle from 5-day-old dSesn-null flies exhibited mitochondrial abnormalities, including a rounded shape, occasional enlargement, and disorganization of cristae, which were also observed in 20-day-old mutants. Mitochondrial dysfunction can result in excessive generation of ROS leading to other abnormalities. dSesn-null muscles exhibited increased accumulation of ROS, revealed by more intense DHE fluorescence and reduced cis-aconitase activity, which was associated with muscle cell death. Furthermore, the muscle defects were prevented by vitamin E feeding, underscoring the role of ROS in muscle degeneration (Lee, 2010).

Expression of exogenous dSesnCS, devoid of redox activity (Budanov, 2004), prevented muscle degeneration, suggesting again that regulation of AMPK-TOR by dSesn, rather than intrinsic redox activity, is of importance. Feeding animals with AMPK activators prevented muscle degeneration in dSesn-null mutants, and depletion of AMPK in skeletal muscles caused severe degeneration of mitochondrial and sarcomeric structures. Treatment of animals with rapamycin also prevented muscle degeneration in dSesn-null flies. Thus, dSesn-dependent control of AMPK-TOR signaling is essential for prevention of mitochondrial dysfunction and maintenance of muscle homeostasis during aging (Lee, 2010).

It was noticed that dSesn-null muscles accumulated polyubiquitin aggregates, which are hallmarks of defective autophagy. To test whether decreased autophagy brought about by excessive and prolonged TOR activity might cause muscle degeneration, expression was silenced of ATG1, an essential component of the autophagic machinery, which is inhibited by TOR. This caused a decline in cardiac performance, as well as degeneration and mitochondrial abnormalities in skeletal muscle. These results suggest that TOR up-regulation caused by dSesn loss inhibits autophagy needed to eliminate ROS-producing dysfunctional mitochondria, which may contribute to muscle degeneration. Consistent with this view, ATG1 silencing resulted in ROS accumulation in wing discs (Lee, 2010).

These results identify Sesn as a negative feedback regulator of TOR function. In mammalian cells, increased expression of mSesns in response to genotoxic stress leads to inhibition of TOR activity through activation of AMPK (Budanov, 2008). This study now shows that transcription of the dSesn gene is increased upon chronic TOR activation through JNK and FoxO in a manner dependent on ROS accumulation. Although transient InR activation inhibits FoxO through its phosphorylation by AKT, this study finds that chronic TOR activation overcomes this inhibition and results in nuclear translocation of FoxO, which increases dSesn transcription. In turn, dSesn suppresses metabolic dysfunction and age-related tissue degeneration brought about by hyperactivated TOR. Although dSesn can inhibit TOR-stimulated cell growth, this analysis points to its most important function being the maintenance of metabolic homeostasis and prevention of TOR-induced tissue degeneration. The three major functions of dSesn revealed by this study -- suppression of lipid accumulation, prevention of cardiac malfunction, and protection of muscle from age-related degeneration -- are adversely affected by obesity, lack of exercise, and aging, which make a disproportional contribution to health problems in developed and rapidly developing societies (Lee, 2010).

Whereas TOR controls cell growth mostly through inhibition of 4E-BP and activation of S6K kinase, its ability to induce dSesn expression depends on ROS accumulation, which the results suggest is a pathophysiological aberration caused by TOR hyperactivation that is normally antagonized by dSesn. However, the previously described redox function of Sesn (Budanov, 2004) is not required for its protective role. TOR-induced accumulation of ROS has been observed in yeast and hematopoietic cells, but the molecular mechanism underlying this phenomenon and its physiological and pathophysiological importance were unknown. The current results suggest that TOR-stimulated production of ROS, which is needed for accumulation of dSesn, is independent of two of the major TOR targets (4E-BP and S6K) and instead may result from TOR-mediated inhibition of physiological autophagy, a process that eliminates ROS-producing dysfunctional mitochondria. Nonetheless, inhibition of 4E-BP also contributes to the pro-aging effects of TOR by suppressing translation of several mitochondrial proteins and by accelerating age-related cardiac malfunction at young ages, which is reminiscent of the observed cardiac defects seen in dSesn-null flies. Although TOR activates SREBP (Dobrosotskaya, 2002), which may contribute to lipid accumulation in dSesn-null flies, autophagy promotes lipid elimination (Singh, 2009). Thus, decreased autophagy may also contribute to triglyceride accumulation. Hence, the different degenerative phenotypes exhibited by dSesn-null flies are due to the cumulative effects of several biochemical and cell biological defects caused by hyperactive TOR, including reduced autophagy and reduced function of 4E-BP. Both basal physiologic autophagy and 4E-BP function are enhanced by calorie restriction, which prevents aging-related pathologies. In the future, it will be of interest to determine the contribution of Sesn to these antiaging effects (Lee, 2010).

p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling

The tumor suppressor p53 (see Drosophila p53) is activated upon genotoxic and oxidative stress and in turn inhibits cell proliferation and growth through induction of specific target genes. Cell growth is positively regulated by mTOR, whose activity is inhibited by the TSC1:TSC2 complex. Although genotoxic stress has been suggested to inhibit mTOR via p53-mediated activation of mTOR inhibitors, the precise mechanism of this link was unknown. This study demonstrates that the products of two p53 target genes, Sestrin1 and Sestrin2, activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR. Correspondingly, Sestrin2-deficient mice fail to inhibit mTOR signaling upon genotoxic challenge. Sestrin1 and Sestrin2 therefore provide an important link between genotoxic stress, p53 and the mTOR signaling pathway (Budanov, 2008).

The mTOR signaling pathway is a central regulator of cell growth and survival. It is therefore not surprising that adverse environmental conditions negatively regulate cell growth by inhibiting mTOR. In addition to nutrient limitation, mTOR activity is negatively regulated by genotoxic stress and hypoxia, conditions that activate tumor suppressor p53. The ability of p53 to inhibit mTOR signaling is in line with its function as a negative regulator of cell growth and proliferation. The results described above strongly suggest that the ability of p53 to inhibit mTOR signaling depends on two of its target genes: Sesn1 and Sesn2 (Budanov, 2008).

The Sestrins belong to a small and evolutionary conserved family composed of 3 members in mammals, of which Sesn1 and 2 are stress inducible and p53 regulated (Budanov, 2002; Velasco-Miguel, 1999). The ability of Sesn1/2 to inhibit cell growth and proliferation was attributed to their redox activity (Budanov, 2004). The present work, however, demonstrates that Sesn1/2 are potent inhibitors of mTOR signaling, acting in a manner that does not depend on their redox activity, which only makes a partial contribution to their growth inhibitory activity. Sesn1 and 2 inhibit TORC1 activity towards p70S6K and 4E-BP1 in a variety of human and mouse cell lines, as well as in mouse liver. Notably, the ability of the hepatocarcinogen DEN to inhibit S6 phosphorylation is restricted to zone 3 hepatocytes, which are the main site in which it undergoes metabolic activation to become a potent alkylating agent, and this inhibitory activity is Sesn2-dependent. By inhibiting 4E-BP1 phosphorylation, Sesn2 enhances its interaction with eIF-4E and inhibits expression of growth regulatory proteins, such as cyclin D1 and c-Myc, whose translation is eIF-4E-dependent and sensitive to 4E-BP1 phosphorylation (Budanov, 2008).

The Sestrins impact TORC1 activity through the TSC1:TSC2 complex. Being a GAP for Rheb, the direct activator of TORC1, the TSC1:TSC2 complex is a central regulator of mTOR signaling. Sesn2 expression decreases Rheb GTP loading and the ability of both Sesn1 and Sesn2 to inhibit mTOR signaling is TSC2-dependent. One way to regulate TSC1:TSC2 GAP activity is through TSC2 phosphorylation, but other modes of regulation may also exist. Although the Sestrins have no effect on ERK and its target RSK or GSK3β, which can all serve as TSC2 kinases, they stimulate the activity of AMPK, a major TSC2 kinase. Furthermore, Sestrin expression enhanced TSC2 phosphorylation in live cells and this effect required the N-terminus of Sesn2, which mediates AMPKα binding. Sesn2 did not stimulate TSC1 phosphorylation and Sesn2-activated AMPK did not phosphorylate TSC1 (Budanov, 2008).

Importantly, the mTOR inhibitory activity of Sesn1/2 depends on AMPKα, whose phosphorylation at the activation loop was enhanced upon Sestrin expression. Inhibition of AMPK using compound C as well as shRNA silencing of AMPKα1 attenuated the ability of Sesn2 to inhibit mTOR signaling. Co-immunoprecipitation and gel filtration analyses revealed an interaction between Sesn2 and AMPKα, suggesting that Sestrins are engaged in formation of a large protein complex containing AMPK and TSC1:TSC2. It is proposed that Sesn1/2 induction in response to genotoxic stress results in binding of Sestrins, most likely as dimers, to AMPK and TSC1:TSC2, as well as auto-activation of AMPK through a mechanism based on induced proximity. In addition to activation of AMPK the Sestrins recruit it to phosphorylate TSC2. Phosphorylation of TSC2 correlates with enhancement of its GAP activity that leads to inhibition of Rheb and mTOR (Budanov, 2008).

Importantly, ample and clear evidence was obtained that Sesn1/2 are critical mediators of p53's ability to inhibit mTOR signaling. Using shRNA-mediated silencing it was found that both Sesn1 and Sesn2 participate in mTOR inhibition upon p53 activation in human cancer cells. Furthermore, disruption of the Sesn2 gene in mice attenuated the inhibition of p70S6K activity by the DNA-damaging agents: camptothecin in fibroblasts and DEN in hepatocytes. In both cases inhibition of p70S6K was p53-mediated, but unlike the p53 deficiency, the absence of Sesn2 has no effect on induction of p21Waf1, another p53 target gene. Thus, Sesn2 (and presumably Sesn1) seems to mediate only one aspect of p53 signaling -- inhibition of mTOR. Correspondingly, the growth-inhibitory activity of Sesn2 is not as strong as that of p53, which has additional targets with anti-proliferative activity, such as p21Waf1 (Budanov, 2008).

p53 deficiency and activation of mTOR signaling are hallmarks of human cancer. Several mechanisms account for mTOR activation in cancer, including activation of Ras, PI3K and AKT and inactivation of tumor suppressors that negatively regulate these molecules: PTEN, TSC1, TSC2 and LKB1. Although p53 can induce expression of several negative regulators of mTOR, including PTEN, TSC2, AMPKβ1 and IGF-BP3 in a cell type-dependent manner, the results demonstrate that p53-mediated inhibition of mTOR depends mainly on Sesn1 and 2 in mouse fibroblasts and certain human cancer cell lines and on Sesn2 in mouse liver (Budanov, 2008).

Inhibition of mTOR suppresses cell growth and proliferation. Sesn2 was known to inhibit cell proliferation, but its mechanism of action was heretofore unknown. The results strongly suggest that Sesn1 and Sesn2 exert their growth inhibitory effect via mTOR and may cooperate with other anti-proliferative p53 targets, such as p21Waf1. Interestingly, the SESN1 (6q21) and SESN2 (1p35) loci are frequently deleted in a variety of human cancers, suggesting they harbor one or more tumor-suppressors. Sesn2 deficiency was found to render murine fibroblasts more susceptible to oncogenic transformation and this effect may depend on mTOR inhibition. Hence, SESN1 and SESN2 may indeed be important components of the tumor suppressor network activated by p53 (Budanov, 2008).

In summary, while more remains to be learned about Sestrin biology and mechanism of action, the results establish these proteins as critical links between p53 and mTOR that enable p53 to inhibit cell growth (Budanov, 2008).

Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling

Mechanistic target of rapamycin complex 1 (mTORC1) (see Drosophila Tor) integrates diverse environmental signals to control cellular growth and organismal homeostasis. In response to nutrients, Rag GTPases (see Drosophila RagA-B) recruit mTORC1 to the lysosome to be activated, but how Rags are regulated remains incompletely understood. This study shows 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 (Peng, 2014).


Search PubMed for articles about Drosophila Sestrin

Budanov, A. V., et al. (2002). Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21: 6017-31. PubMed ID: 12203114

Budanov, A. V., et al. (2004). Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304: 596-600. PubMed ID: 15105503

Budanov, A. V. and Karin, M. (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134: 451-60. PubMed ID: 18692468

Dobrosotskaya, I. Y., et al. (2002). Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science 296: 879-83. PubMed ID: 11988566

Greer, E. L. and Brunet, A. (2005). FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24: 7410-25. PubMed ID: 16288288

Lee, J. H., et al. (2010). Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327: 1223-1228. PubMed ID: 20203043

Peng, M., Yin, N. and Li, M. O. (2014). Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159: 122-133. PubMed ID: 25259925

Singh, R. et al. (2009). Autophagy regulates lipid metabolism. Nature 458: 1131-5. PubMed ID: 19339967

Velasco-Miguel. S., et al. (1999). PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 18: 127-37. PubMed ID: 9926927

Biological Overview

date revised: 5 April 2021

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