Serine- and Threonine/Valine-Dependent Activation of PDK and Tor Orthologs Converge on Sch9 to Promote Aging

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Dietary restriction extends longevity in organisms ranging from bacteria to mice and protects primates from a variety of diseases, but the contribution of each dietary component to aging is poorly understood. Here we demonstrate that glucose and specific amino acids promote stress sensitization and aging through the differential activation of the Ras/cAMP/PKA, PKH1/2 and Tor/S6K pathways. Whereas glucose sensitized cells through a Ras-dependent mechanism, threonine and valine promoted cellular sensitization and aging primarily by activating the Tor/S6K pathway and serine promoted sensitization via PDK1 orthologs Pkh1/2. Serine, threonine and valine activated a signaling network in which Sch9 integrates TORC1 and Pkh signaling via phosphorylation of threonines 570 and 737 and promoted intracellular relocalization and transcriptional inhibition of the stress resistance protein kinase Rim15. Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals.

Vyšlo v časopise: Serine- and Threonine/Valine-Dependent Activation of PDK and Tor Orthologs Converge on Sch9 to Promote Aging. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004113
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004113

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1. FontanaL, PartridgeL, LongoVD (2010) Extending healthy life span from yeast to humans. Science 328 : 321–326.

2. PamplonaR, BarjaG (2006) Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection. Biochim. Biophys Acta 1757 : 496–508.

3. TrepanowskiJF, CanaleRE, MarshallKE, KabirMM, BloomerRJ (2011) Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings. Nutr J 10 : 107.

4. OcampoA, LiuJ, SchroederEA, ShadelGS, BarrientosA (2012) Mitochondrial respiratory thresholds regulate yeast chronological life span and its extension by caloric restriction. Cell Metab 16(1): 55–67.

5. LoewithR, HallMN (2011) Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189(4): 1177–201.

6. WeiM, FabrizioP, HuJ, GeH, ChengC, et al. (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4: e13.

7. LongoVD, FontanaL (2010) Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 31 : 89–98.

8. Longo VD (1997) The Pro-senescence role of Ras2 in the chronological lifespan of yeast (Los Angeles: University of California Los Angeles).

9. LongoVD, EllerbyLM, BredesenDE, ValentineJS, GrallaEB (1997) Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J Cell Biol 137 : 1581–1588.

10. MartinezMJ, RoyS, ArchulettaAB, WentzellPD, Anna-ArriolaSS, et al. (2004) Genomic analysis of stationary-phase and exit in Saccharomyces cerevisiae: gene expression and identification of novel essential genes. Mol Biol Cell 15 : 5295–5305.

11. SlatteryMG, HeidemanW (2007) Coordinated regulation of growth genes in Saccharomyces cerevisiae. Cell Cycle 6 : 1210–1219.

12. ZamanS, LippmanSI, ZhaoX, BroachJR (2008) How Saccharomyces responds to nutrients. Annu Rev Genet 42 : 27–81.

13. ZhangA, ShenY, GaoW, DongJ (2011) Role of Sch9 in regulating Ras-cAMP signal pathway in Saccharomyces cerevisiae. FEBS Lett 585 : 3026–3032.

14. Rubio-TexeiraM, Van ZeebroeckG, VoordeckersK, TheveleinJM (2010) Saccharomyces cerevisiae plasma membrane nutrient sensors and their role in PKA signaling. FEMS Yeast Res 10 : 134–149.

15. TheveleinJM, De WindeJH (1999) Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol 33 : 904–918.

16. OzcanS, DoverJ, JohnstonM (1998) Glucose sensing and signaling by two glucose receptors in the yeast Saccharomyces cerevisiae. EMBO J 17 : 2566–2573.

17. DonatonMC, HolsbeeksI, LagatieO, Van ZeebroeckG, CrauwelsM, et al. (2003) The Gap1 general amino acid permease acts as an amino acid sensor for activation of protein kinase A targets in the yeast Saccharomyces cerevisiae. Mol Microbiol 50 : 911–929.

18. GiotsF, DonatonMC, TheveleinJM (2003) Inorganic phosphate is sensed by specific phosphate carriers and acts in concert with glucose as a nutrient signal for activation of the protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol 47 : 1163–1181.

19. Van NulandA, VandormaelP, DonatonM, AlenquerM, LourençoA, et al. (2006) Ammonium permease-based sensing mechanism for rapid ammonium activation of the proteinkinase A pathway in yeast. Mol Microbiol 59 : 1485–1505.

20. JiangJC, JarugaE, RepnevskayaMV, JazwinskiSM (2000) An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J 14 : 2135–2137.

21. ZaborskeJM, WuX, WekRC, PanT (2010) Selective control of amino acid metabolism by the GCN2 eIF2 kinase pathway in Saccharomyces cerevisiae. BMC Biochem 4 : 11–29.

22. ChurchMW, JenKL, AnumbaJI, JacksonDA, AdamsBR, et al. (2010) Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring. Neurotoxicol Teratol 32 : 171–81.

23. GrandisonRC, PiperMD, PartridgeL (2009) Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462 : 1061–1064.

24. ShelleyP, Tarry-AdkinsJ, Martin-GronertM, PostonL, HealesS, et al. (2007) Rapid neonatal weight gain in rats results in a renal ubiquinone (CoQ) deficiency associated with premature death. Mech Ageing Dev 128 : 681–687.

25. SkorupaDA, DervisefendicA, ZwienerJ, PletcherSD (2008) Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster. Aging Cell 7 : 478–490.

26. WoloszynekJC, KovacsA, OhlemillerKK, RobertsM, SandsMS (2009) Metabolic adaptations to interrupted glycosaminoglycan recycling. J Biol Chem 284 : 29684–91.

27. BruhatA, ChérasseY, ChaverouxC, MaurinAC, JousseC, et al. (2009) Amino acids as regulators of gene expression in mammals: molecular mechanisms. Biofactors 35 : 249–257.

28. ChaverouxC, Lambert-LanglaisS, CherasseY, AverousJ, ParryL, et al. (2010) Molecular mechanisms involved in the adaptation to amino acid limitation in mammals. Biochimie 92 : 736–745.

29. JousseC, BruhatA, FafournouxP (1999) Amino acid regulation of gene expression. Curr Opin Clin Nutr Metab Care 2 : 297–301.

30. AvruchJ, LongX, Ortiz-VegaS, RapleyJ, PapageorgiouA, et al. (2009) Amino acid regulation of TOR complex1. Am J Physiol Endocrinol Metab 296 : 592–602.

31. SenguptaS, PetersonTR, SabatiniDM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40 : 310–322.

32. HaraK, YonezawaK, WengQP, KozlowskiMT, BelhamC, et al. (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273 : 14484–14494.

33. UrbanJ, SoulardA, HuberA, LippmanS, MukhopadhyayD, et al. (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26 : 663–674.

34. VoordeckersK, KimpeM, HaesendonckxS, LouwetW, VerseleM, et al. (2011) Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1–3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)/S6K ortholog Sch9. J Biol Chem 286 : 22017–22027.

35. HuangX, LiuJ, DicksonRC (2012) Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet 8: e1002493.

36. FriantS, LombardiR, SchmelzleT, HallMN, RiezmanH (2001) Sphingoid base signaling via Pkh kinases is required for endocytosis in yeast. EMBO J 20 : 6783–6792.

37. DicksonRC (2010) Roles for sphingolipids in Saccharomyces cerevisiae. Adv Exp Med Biol 688 : 217–31.

38. MartinDE, HallMN (2005) The expanding TOR signaling network. Curr Opin Cell Biol 17 : 158–166.

39. Van ZeebroeckG, KimpeM, VandormaelP, TheveleinJM (2011) A split-ubiquitin two-hybrid screen for proteins physically interacting with the yeast amino acid transceptor Gap1 and ammonium transceptor Mep2. PLoS One 6: e24275.

40. FischerC, ValeriusO, RupprechtH, DumkowM (2008) Post transcriptional regulation of FLO11 upon amino acid starvation in Saccharomyces cerevisiae. FEMS Yeast Res 8 : 225–236.

41. Van de VeldeS, TheveleinJM (2008) Cyclic AMP-protein kinase A and Snf1 signaling mechanisms underlie the superior potency of sucrose for induction of filamentation in Saccharomyces cerevisiae. Eukaryot Cell 7 : 286–293.

42. AmitranoAA, SaenzDA, RamosEH (1997) GAP1 activity is dependent on cAMP in Saccharomyces cerevisiae. FEMS Microbiol Lett 151 : 131–133.

43. GarrettJM (2008) Amino acid transport through the Saccharomyces cerevisiae Gap1 permease is controlled by the Ras/cAMPpathway. Int J Biochem Cell Biol 40 : 496–502.

44. SoulardA, CremonesiA, MoesS, SchützF, JenöP, et al. (2010) The rapamycin-sensitive phosphoproteome reveals that TOR controls protein kinase A toward some but not all substrates. Mol Biol Cell 21 : 3475–86.

45. LongoVD, ShadelGS, KaeberleinM, KennedyB (2012) Replicative and Chronological Aging in Saccharomyces cerevisiae. Cell Metab 16 : 18–31.

46. LongoVD, FabrizioP (2012) Chronological Aging in Saccharomyces cerevisiae. Subcell Biochem 57 : 101–121.

47. BoerVM, AminiS, BotsteinD (2008) Influence of genotype and nutrition on survival and metabolism of starving yeast. Proc Natl Acad Sci USA 105 : 6930–6935.

48. KlosinskaMM, CrutchfieldCA, BradleyPH, RabinowitzJD, BroachJR (2011) Yeast cells can access distinct quiescent states. Genes Dev 25 : 336–349.

49. LinSJ, KaeberleinM, AndalisAA, SturtzLA, DefossezPA, et al. (2002) Calorie restriction extends Saccharomyces cerevisiae life span by increasing respiration. Nature 418 : 344–8.

50. WeiM, FabrizioP, MadiaF, HuJ, GeH, et al. (2009) Tor1/Sch9-regulated carbon source substitution is as effectiveas calorie restriction in life span extension. PLoS Genet 5: e1000467.

51. BurtnerCR, MurakamiCJ, KennedyBK, KaeberleinM (2009) A molecular mechanism of chronological aging in yeast. Cell Cycle 8(8): 1256–1270.

52. MirisolaMG, LongoVD (2012) Acetic acid and acidification accelerate chronological and replicative aging in yeast. Cell Cycle 11(19): 3532–3.

53. HuJ, WeiM, MirisolaMG, LongoVD (2013) Assessing chronological aging in Saccharomyces cerevisiae. Methods Mol Biol 965 : 463–72.

54. KimJ, GuanKL (2011) Amino acid signaling in TOR activation. Annu Rev Biochem 80 : 1001–32.

55. BayascasJR (2010) PDK1: the major transducer of PI 3-kinase actions. Curr. Top Microbiol Immunol 346 : 9–29.

56. DongLQ, RamosFJ, WickMJ, LimMA, GuoZ, et al. (2002) Cloning and characterization of a testis and brain-specific isoform of mouse 3′-phosphoinositide-dependent protein kinase-1, mPDK-1 beta. Biochem Biophys Res Commun 294 : 136–144.

57. GanX, WangJ, SuB, WuD (2011) Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 286 : 10998–1002.

58. MoraA, KomanderD, Van AaltenDM, AlessiDR (2004) PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol 15 : 161–70.

59. PolakP, HallMN (2009) mTOR and the control of whole body metabolism. Curr Opin Cell Biol 21 : 209–218.

60. LiuK, ZhangX, LesterRL, DicksonRC (2005) The sphingoid long chain base phytosphingosine activates AGC-type protein kinases in Saccharomyces cerevisiae including Ypk1, Ypk2, and Sch9. J Biol Chem 280 : 22679–87.

61. RoelantsFM, TorrancePD, ThornerJ (2004) Differential roles of PDK1 -⁠ and PDK2-phosphorylation sites in the yeast AGC kinases Ypk1, Pkc1 and Sch9. Microbiology 150 : 3289–304.

62. CrespoJL, PowersT, FowlerB, HallMN (2002) The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine. Proc Natl Acad Sci USA 99 : 6784–6789.

63. PowersRW3rd, KaeberleinM, CaldwellSD, KennedyBK, FieldsS (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20 : 174–184.

64. RichieJPJr, LeutzingerY, ParthasarathyS, MalloyV, OrentreichN, et al. (1994) Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J 8(15): 1302–1307.

65. MalloyVL, KrajcikRA, BaileySJ, HristopoulosG, PlummerJD, et al. (2006) Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell 5(4): 305–314.

66. MiyakeY, KozutsumiY, NakamuraS, FujitaT, KawasakiT (1995) Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem Biophys Res Commun 211 : 396–403.

67. CameroniE, HuloN, RoosenJ, WinderickxJ, De VirgilioC (2004) The novel yeast PAS kinase Rim 15 orchestrates G0-associated antioxidant defense mechanisms. Cell Cycle 3 : 462–8.

68. FabrizioP, PozzaF, PletcherSD, GendronCM, LongoVD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292 : 288–90.

69. PedruzziI, DuboulozF, CameroniE, WankeV, RoosenJ, et al. (2003) TOR and PKA signaling pathways converge on the protein kinase Rim15 to control entry into G0. Mol Cell 12 : 1607–1613.

70. SwisherKD, ParkerR (2010) Localization to, and effects of Pbp1, Pbp4, Lsm12, Dhh1, and Pab1 on stress granules in Saccharomyces cerevisiae. PLoS One 5(4): e10006.

71. SchmittAP, McEnteeK (1996) Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93 : 5777–5782.

72. Martínez-PastorMT, MarchlerG, SchüllerC, Marchler-BauerA, RuisH, et al. (1996) The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J 15 : 2227–2235.

73. GörnerW, DurchschlagE, Martinez-PastorMT, EstruchF, AmmererG, et al. (1998) Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev 12 : 586–597.

74. DeRisiJL, IyerVR, BrownPO (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278 : 680–6.

75. PedruzziI, BürckertN, EggerP, De VirgilioC (2000) Saccharomyces cerevisiae Ras/cAMP pathway controls post-diauxic shift element-dependent transcription through the zinc finger protein Gis1. EMBO J 19 : 2569–2579.

76. YuY, NeimanAM, SternglanzR (2010) The JmjC domain of Gis1 is dispensable for transcriptional activation. FEMS Yeast Res 10 : 793–801.

77. De MarteML, EnescoHE (1986) Influence of low tryptophan diet on survival and organ growth in mice. Mech Ageing Dev 36 : 161.

78. MillerRA, BuehnerG, ChangY, Harper JM SiglerR, et al. (2005) Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, altersglucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4 : 119.

79. OrentreichN, MatiasJR, De FeliceA, ZimmermanJA (1993) Low methionine ingestion by rats extends life span. J Nutr 123 : 269–74.

80. ZimmermanJA, MalloyV, KrajcikR, OrentreichN (2003) Nutritional control of aging. ExpGerontol 38 : 47–52.

81. SancakY, PetersonTR, ShaulYD, LindquistRA, ThoreenCC, et al. (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320 : 1496–501.

82. SancakY, Bar-PeledL, ZoncuR, MarkhardAL, NadaS, et al. (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino-acids. Cell 141 : 290–303.

83. IkushiroH, HayashiH (2011) Mechanistic enzymology of serine palmitoyl transferase. Biochim Biophys Acta 1814 : 1474–80.

84. BrachmannCB, DaviesA, CostGJ, CaputoE, LiJ, et al. (1998) Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast 14 : 115–132.

85. LaemmliUK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259): 680–685.

86. VoordeckersK, KimpeM, HaesendonckxS, LouwetW, VerseleM, TheveleinJM (2011) Yeast 3-phosphoinositide-dependent protein kinase-1 (PDK1) orthologs Pkh1–3 differentially regulate phosphorylation of protein kinase A (PKA) and the protein kinase B (PKB)/S6K ortholog Sch9. J Biol Chem 286(25): 22017–22027.