DAF-16/FoxO Directly Regulates an Atypical AMP-Activated Protein Kinase Gamma Isoform to Mediate the Effects of Insulin/IGF-1 Signaling on Aging in


The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved.


Vyšlo v časopise: DAF-16/FoxO Directly Regulates an Atypical AMP-Activated Protein Kinase Gamma Isoform to Mediate the Effects of Insulin/IGF-1 Signaling on Aging in. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004109
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004109

Souhrn

The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved.


Zdroje

1. FriedmanDB, JohnsonTE (1988) Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol 43: B102–109.

2. KenyonC, ChangJ, GenschE, RudnerA, TabtiangR (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366: 461–464.

3. KimuraKD, TissenbaumHA, LiuY, RuvkunG (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277: 942–946.

4. KenyonCJ (2010) The genetics of ageing. Nature 464: 504–512.

5. GemsD, PartridgeL (2013) Genetics of longevity in model organisms: debates and paradigm shifts. Annu Rev Physiol 75: 621–644.

6. LinK, HsinH, LibinaN, KenyonC (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28: 139–145.

7. OggS, ParadisS, GottliebS, PattersonGI, LeeL, et al. (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994–999.

8. McElweeJJ, SchusterE, BlancE, ThomasJH, GemsD (2004) Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem 279: 44533–44543.

9. MurphyCT, McCarrollSA, BargmannCI, FraserA, KamathRS, et al. (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424: 277–283.

10. MurphyCT, LeeSJ, KenyonC (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A 104: 19046–19050.

11. Halaschek-WienerJ, KhattraJS, McKayS, PouzyrevA, StottJM, et al. (2005) Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. Genome Res 15: 603–615.

12. OhSW, MukhopadhyayA, DixitBL, RahaT, GreenMR, et al. (2006) Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat Genet 38: 251–257.

13. DongMQ, VenableJD, AuN, XuT, ParkSK, et al. (2007) Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. Science 317: 660–663.

14. LeeSJ, MurphyCT, KenyonC (2009) Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10: 379–391.

15. McElweeJ, BubbK, ThomasJH (2003) Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2: 111–121.

16. VilchezD, MorantteI, LiuZ, DouglasPM, MerkwirthC, et al. (2012) RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489: 263–268.

17. GemsD, McElweeJJ (2005) Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech Ageing Dev 126: 381–387.

18. HsuAL, MurphyCT, KenyonC (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300: 1142–1145.

19. CohenE, BieschkeJ, PerciavalleRM, KellyJW, DillinA (2006) Opposing activities protect against age-onset proteotoxicity. Science 313: 1604–1610.

20. Ben-ZviA, MillerEA, MorimotoRI (2009) Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 106: 14914–14919.

21. VanfleterenJR (1993) Oxidative stress and ageing in Caenorhabditis elegans. Biochem J 292(Pt 2): 605–608.

22. SchusterE, McElweeJJ, TulletJM, DoonanR, MatthijssensF, et al. (2010) DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO. Mol Syst Biol 6: 399.

23. HardieDG, CarlingD (1997) The AMP-activated protein kinase–fuel gauge of the mammalian cell? Eur J Biochem 246: 259–273.

24. XiaoB, SandersMJ, UnderwoodE, HeathR, MayerFV, et al. (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472: 230–233.

25. ApfeldJ, O'ConnorG, McDonaghT, DiStefanoPS, CurtisR (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18: 3004–3009.

26. CurtisR, O'ConnorG, DiStefanoPS (2006) Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5: 119–126.

27. SelmanC, TulletJM, WieserD, IrvineE, LingardSJ, et al. (2009) Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326: 140–144.

28. GreerEL, DowlatshahiD, BankoMR, VillenJ, HoangK, et al. (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17: 1646–1656.

29. MairW, MorantteI, RodriguesAP, ManningG, MontminyM, et al. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470: 404–408.

30. StenesenD, SuhJM, SeoJ, YuK, LeeKS, et al. (2013) Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab 17: 101–112.

31. FunakoshiM, TsudaM, MuramatsuK, HatsudaH, MorishitaS, et al. (2011) A gain-of-function screen identifies wdb and lkb1 as lifespan-extending genes in Drosophila. Biochem Biophys Res Commun 405: 667–672.

32. SlackC, FoleyA, PartridgeL (2012) Activation of AMPK by the putative dietary restriction mimetic Metformin is insufficient to extend lifespan in Drosophila. PLoS One 7: e47699.

33. SalminenA, KaarnirantaK (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11: 230–241.

34. GreerEL, OskouiPR, BankoMR, ManiarJM, GygiMP, et al. (2007) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282: 30107–30119.

35. PanDA, HardieDG (2002) A homologue of AMP-activated protein kinase in Drosophila melanogaster is sensitive to AMP and is activated by ATP depletion. Biochem J 367: 179–186.

36. HardieDG, CarlingD, GamblinSJ (2011) AMP-activated protein kinase: also regulated by ADP? Trends Biochem Sci 36: 470–477.

37. XiaoB, HeathR, SaiuP, LeiperFC, LeoneP, et al. (2007) Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449: 496–500.

38. AradM, BensonDW, Perez-AtaydeAR, McKennaWJ, SparksEA, et al. (2002) Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 109: 357–362.

39. ZouL, ShenM, AradM, HeH, LofgrenB, et al. (2005) N488I mutation of the gamma2-subunit results in bidirectional changes in AMP-activated protein kinase activity. Circ Res 97: 323–328.

40. LuptakI, ShenM, HeH, HirshmanMF, MusiN, et al. (2007) Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J Clin Invest 117: 1432–1439.

41. AhmadF, AradM, MusiN, HeH, WolfC, et al. (2005) Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation 112: 3140–3148.

42. SandersMJ, GrondinPO, HegartyBD, SnowdenMA, CarlingD (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403: 139–148.

43. DanielT, CarlingD (2002) Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome. J Biol Chem 277: 51017–51024.

44. HawleySA, RossFA, ChevtzoffC, GreenKA, EvansA, et al. (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11: 554–565.

45. BudovskayaYV, WuK, SouthworthLK, JiangM, TedescoP, et al. (2008) An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134: 291–303.

46. DePinaAS, IserWB, ParkSS, MaudsleyS, WilsonMA, et al. (2011) Regulation of Caenorhabditis elegans vitellogenesis by DAF-2/IIS through separable transcriptional and posttranscriptional mechanisms. BMC Physiol 11: 11.

47. DepuydtG, XieF, PetyukVA, ShanmugamN, SmoldersA, et al. (2013) Reduced insulin/IGF-1 signaling and dietary restriction inhibit translation but preserve muscle mass in Caenorhabditis elegans. Mol Cell Proteomics. 12: 3624–39.

48. FuruyamaT, NakazawaT, NakanoI, MoriN (2000) Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J 349: 629–634.

49. TroemelER, ChuSW, ReinkeV, LeeSS, AusubelFM, et al. (2006) p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans. PLoS Genet 2: e183.

50. GoldenTR, MelovS (2004) Microarray analysis of gene expression with age in individual nematodes. Aging Cell 3: 111–124.

51. Hunt-NewburyR, ViveirosR, JohnsenR, MahA, AnastasD, et al. (2007) High-throughput in vivo analysis of gene expression in Caenorhabditis elegans. PLoS Biol 5: e237.

52. SimmerF, TijstermanM, ParrishS, KoushikaSP, NonetML, et al. (2002) Loss of the putative RNA-directed RNA polymerase RRF-3 makes C. elegans hypersensitive to RNAi. Curr Biol 12: 1317–1319.

53. KwonES, NarasimhanSD, YenK, TissenbaumHA (2010) A new DAF-16 isoform regulates longevity. Nature 466: 498–502.

54. ZhangP, JudyM, LeeSJ, KenyonC (2013) Direct and indirect gene regulation by a life-extending FOXO protein in C. elegans: roles for GATA factors and lipid gene regulators. Cell Metab 17: 85–100.

55. HamiltonSR, StapletonD, O'DonnellJBJr, KungJT, DalalSR, et al. (2001) An activating mutation in the gamma1 subunit of the AMP-activated protein kinase. FEBS Lett 500: 163–168.

56. LibinaN, BermanJR, KenyonC (2003) Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115: 489–502.

57. AlcedoJ, KenyonC (2004) Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41: 45–55.

58. GollobMH (2003) Glycogen storage disease as a unifying mechanism of disease in the PRKAG2 cardiac syndrome. Biochem Soc Trans 31: 228–231.

59. NarbonneP, RoyR (2009) Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457: 210–214.

60. AlonU (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8: 450–461.

61. AlicN, AndrewsTD, GiannakouME, PapatheodorouI, SlackC, et al. (2011) Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. Mol Syst Biol 7: 502.

62. EijkelenboomA, MokryM, de WitE, SmitsLM, PoldermanPE, et al. (2013) Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling. Mol Syst Biol 9: 638.

63. TothovaZ, KolliparaR, HuntlyBJ, LeeBH, CastrillonDH, et al. (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325–339.

64. PaikJH, KolliparaR, ChuG, JiH, XiaoY, et al. (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128: 309–323.

65. BakkerWJ, van DijkTB, Parren-van AmelsvoortM, KolbusA, YamamotoK, et al. (2007) Differential regulation of Foxo3a target genes in erythropoiesis. Mol Cell Biol 27: 3839–3854.

66. LutznerN, De-Castro ArceJ, RoslF (2012) Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NF-Y and FOXO transcription factors. PLoS One 7: e32590.

67. HobertO (2002) PCR fusion-based approach to create reporter gene constructs for expression analysis in transgenic C. elegans. Biotechniques 32: 728–730.

68. HoogewijsD, HouthoofdK, MatthijssensF, VandesompeleJ, VanfleterenJR (2008) Selection and validation of a set of reliable reference genes for quantitative sod gene expression analysis in C. elegans. BMC Mol Biol 9: 9 doi:10.1186/1471-2199-9-9

69. MukhopadhyayA, DeplanckeB, WalhoutAJ, TissenbaumHA (2008) Chromatin immunoprecipitation (ChIP) coupled to detection by quantitative real-time PCR to study transcription factor binding to DNA in Caenorhabditis elegans. Nat Protoc 3: 698–709.

70. HsinH, KenyonC (1999) Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399: 362–366.

71. LomsadzeA, Ter-HovhannisyanV, ChernoffYO, BorodovskyM (2005) Gene identification in novel eukaryotic genomes by self-training algorithm. Nucleic Acids Res 33: 6494–6506.

72. EdgarRC (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5: 113.

73. LarkinMA, BlackshieldsG, BrownNP, ChennaR, McGettiganPA, et al. (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23: 2947–2948.

74. UniProtC (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40: D71–75.

75. RanwezV, ClaironN, DelsucF, PouraliS, AubervalN, et al. (2009) PhyloExplorer: a web server to validate, explore and query phylogenetic trees. BMC Evol Biol 9: 108.

76. ZhangH, GaoS, LercherMJ, HuS, ChenWH (2012) EvolView, an online tool for visualizing, annotating and managing phylogenetic trees. Nucleic Acids Res 40: W569–572.

77. DoonanR, McElweeJJ, MatthijssensF, WalkerGA, HouthoofdK, et al. (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22: 3236–3241.

78. Van RaamsdonkJM, HekimiS (2012) Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci U S A 109: 5785–5790.

79. EtchbergerJF, HobertO (2008) Vector-free DNA constructs improve transgene expression in C. elegans. Nat Methods 5: 3.

80. LeeH, ChoJS, LambacherN, LeeJ, LeeSJ, et al. (2008) The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. J Biol Chem 283: 14988–14993.

81. HendersonST, JohnsonTE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11: 1975–1980.

82. PatelDS, Garza-GarciaA, NanjiM, McElweeJJ, AckermanD, et al. (2008) Clustering of genetically defined allele classes in the Caenorhabditis elegans DAF-2 insulin/IGF-1 receptor. Genetics 178: 931–946.

83. TulletJM, HertweckM, AnJH, BakerJ, HwangJY, et al. (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132: 1025–1038.

84. BatemanA (1997) The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem Sci 22: 12–13.

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