High-Resolution Profiling of Stationary-Phase Survival Reveals Yeast Longevity Factors and Their Genetic Interactions

English version České info

Lifespan is influenced by a large number of conserved proteins and gene-regulatory pathways. Here, we introduce a strategy for systematically finding such longevity factors in Saccharomyces cerevisiae and scoring the genetic interactions (epistasis) among these factors. Specifically, we developed an automated competition-based assay for chronological lifespan, defined as stationary-phase survival of yeast populations, and used it to phenotype over 5,600 single- or double-gene knockouts at unprecedented quantitative resolution. We found that 14% of the viable yeast mutant strains were affected in their stationary-phase survival; the extent of true-positive chronological lifespan factors was estimated by accounting for the effects of culture aeration and adaptive regrowth. We show that lifespan extension by dietary restriction depends on the Swr1 histone-exchange complex and that a functional link between autophagy and the lipid-homeostasis factor Arv1 has an impact on cellular lifespan. Importantly, we describe the first genetic interaction network based on aging phenotypes, which successfully recapitulated the core-autophagy machinery and confirmed a role of the human tumor suppressor PTEN homologue in yeast lifespan and phosphatidylinositol phosphate metabolism. Our quantitative analysis of longevity factors and their genetic interactions provides insights into the gene-network interactions of aging cells.

Vyšlo v časopise: High-Resolution Profiling of Stationary-Phase Survival Reveals Yeast Longevity Factors and Their Genetic Interactions. PLoS Genet 10(2): e32767. doi:10.1371/journal.pgen.1004168
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004168

Souhrn

Zdroje

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

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

3. TatarM, KopelmanA, EpsteinD, TuM-P, YinC-M, et al. (2001) A mutant drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292: 107–110.

4. BlüherM, KahnBB, KahnCR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299: 572–574.

5. BishopNA, GuarenteL (2007) Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8: 835–844.

6. KaeberleinM (2010) Lessons on longevity from budding yeast. Nature 464: 513–519.

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

8. MortimerRK, JohnstonJR (1959) Life span of individual yeast cells. Nature 183: 1751–1752.

9. LongoVD, GrallaEB, ValentineJS (1996) Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Journal of Biological Chemistry 271: 12275–12280.

10. MacLeanM, HarrisN, PiperPW (2001) Chronological lifespan of stationary phase yeast cells; a model for investigating the factors that might influence the ageing of postmitotic tissues in higher organisms. Yeast 18: 499–509.

11. FabrizioP, PozzaF, PletcherSD, GendronCM, LongoVD (2001) Regulation of Longevity and Stress Resistance by Sch9 in Yeast. Science 292: 288–290.

12. KaeberleinM, PowersRW, SteffenKK, WestmanEA, HuD, et al. (2005) Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients. Science 310: 1193–1196.

13. 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.

14. CuervoAM (2008) Autophagy and aging: keeping that old broom working. Trends in Genetics 24: 604–612.

15. JakubowskiW, BilinskiT, BartoszG (2000) Oxidative stress during aging of stationary cultures of the yeast Saccharomyces cerevisiae. Free Radical Biology and Medicine 28: 659–664.

16. BarrosMH, BandyB, TaharaEB, KowaltowskiAJ (2004) Higher Respiratory Activity Decreases Mitochondrial Reactive Oxygen Release and Increases Life Span in Saccharomyces cerevisiae. Journal of Biological Chemistry 279: 49883–49888.

17. JazwinskiSM (2005) Yeast longevity and aging–the mitochondrial connection. Mech Ageing Dev 126: 243–248.

18. MerzS, WestermannB (2009) Genome-wide deletion mutant analysis reveals genes required for respiratory growth, mitochondrial genome maintenance and mitochondrial protein synthesis in Saccharomyces cerevisiae. Genome Biol 10: R95.

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

20. MurakamiC, BurtnerC, KennedyB, KaeberleinM (2008) A method for high-throughput quantitative analysis of yeast chronological life span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63: 113.

21. MatecicM, SmithDL, PanX, MaqaniN, BekiranovS, et al. (2010) A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet 6: e1000921.

22. FabrizioP, HoonS, ShamalnasabM, GalbaniA, WeiM, et al. (2010) Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet 6: e1001024.

23. GreshamD, BoerVM, CaudyA, ZivN, BrandtNJ, et al. (2011) System-level analysis of genes and functions affecting survival during nutrient starvation in Saccharomyces cerevisiae. Genetics 187: 299–317.

24. PhillipsP (2008) Epistasis—the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9: 855–867.

25. TongA, LesageG, BaderG, DingH, XuH, et al. (2004) Global mapping of the yeast genetic interaction network. Science 303: 808.

26. PanX, YuanDS, XiangD, WangX, Sookhai-MahadeoS, et al. (2004) A robust toolkit for functional profiling of the yeast genome. Molecular Cell 16: 487.

27. SegrèD, DeLunaA, ChurchG, KishonyR (2005) Modular epistasis in yeast metabolism. Nature Genetics 37: 77–83.

28. SchuldinerM, CollinsS, ThompsonN, DenicV, BhamidipatiA, et al. (2005) Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123: 507–519.

29. CollinsSR, MillerKM, MaasNL, RoguevA, FillinghamJ, et al. (2007) Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature 446: 806–810.

30. St OngeR, ManiR, OhJ, ProctorM, FungE, et al. (2007) Systematic pathway analysis using high-resolution fitness profiling of combinatorial gene deletions. Nature Genetics 39: 199–206.

31. CostanzoM, BaryshnikovaA, BellayJ, KimY, SpearED, et al. (2010) The Genetic Landscape of a Cell. Science 327: 425–431.

32. GuénoléA, SrivasR, VreekenK, WangZZ, WangS, et al. (2012) Dissection of DNA Damage Responses Using Multiconditional Genetic Interaction Maps. Molecular Cell

33. SnitkinES, SegrèD (2011) Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes. PLoS Genetics 7: e1001294.

34. Ryan ColmJ, RoguevA, PatrickK, XuJ, JahariH, et al. (2012) Hierarchical Modularity and the Evolution of Genetic Interactomes across Species. Molecular Cell 46: 691–704.

35. MüllederM, CapuanoF, PirP, ChristenS, SauerU, et al. (2012) A prototrophic deletion mutant collection for yeast metabolomics and systems biology. Nat Biotechnol 30: 1176–1178.

36. BurtnerC, MurakamiC, KennedyB, KaeberleinM (2009) A molecular mechanism of chronological aging in yeast. Cell Cycle 8: 1256.

37. WinzelerEA, ShoemakerDD, AstromoffA, LiangH, AndersonK, et al. (1999) Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285: 901–906.

38. PiperPW (2006) Long-lived yeast as a model for ageing research. Yeast 23: 215–226.

39. AlversAL, FishwickLK, WoodMS, HuD, ChungHS, et al. (2009) Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell 8: 353–369.

40. OnoderaJ, OhsumiY (2004) Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae. J Biol Chem 279: 16071–16076.

41. HerkerE, JungwirthH, LehmannKA, MaldenerC, FrohlichKU, et al. (2004) Chronological aging leads to apoptosis in yeast. J Cell Biol 164: 501–507.

42. FabrizioP, LongoVD (2008) Chronological aging-induced apoptosis in yeast. Biochim Biophys Acta 1783: 1280–1285.

43. LiW, SunL, LiangQ, WangJ, MoW, et al. (2006) Yeast AMID homologue Ndi1p displays respiration-restricted apoptotic activity and is involved in chronological aging. Mol Biol Cell 17: 1802–1811.

44. JazwinskiSM (2005) The retrograde response links metabolism with stress responses, chromatin-dependent gene activation, and genome stability in yeast aging. Gene 354: 22–27.

45. TinkelenbergAH, LiuY, AlcantaraF, KhanS, GuoZ, et al. (2000) Mutations in yeast ARV1 alter intracellular sterol distribution and are complemented by human ARV1. J Biol Chem 275: 40667–40670.

46. SwainE, StukeyJ, McDonoughV, GermannM, LiuY, et al. (2002) Yeast cells lacking the ARV1 gene harbor defects in sphingolipid metabolism. Complementation by human ARV1. J Biol Chem 277: 36152–36160.

47. BehCT, RineJ (2004) A role for yeast oxysterol-binding protein homologs in endocytosis and in the maintenance of intracellular sterol-lipid distribution. J Cell Sci 117: 2983–2996.

48. GeorgievAG, JohansenJ, RamanathanVD, SereYY, BehCT, et al. (2013) Arv1 Regulates PM and ER Membrane Structure and Homeostasis But is Dispensable for Intracellular Sterol Transport. Traffic 14: 912–921.

49. LongoV, ShadelG, KaeberleinM, KennedyB (2012) Replicative and Chronological Aging in Saccharomyces cerevisiae. Cell metabolism 16: 18.

50. FabrizioP, LongoV (2003) The chronological life span of Saccharomyces cerevisiae. Aging Cell 2: 73–81.

51. KroganNJ, KeoghM-C, DattaN, SawaC, RyanOW, et al. (2003) A Snf2 Family ATPase Complex Required for Recruitment of the Histone H2A Variant Htz1. Molecular Cell 12: 1565–1576.

52. Kamada Y, Sekito T, Ohsumi Y, Thomas G, Sabatini DM, et al. (2004) Autophagy in Yeast: A TOR-Mediated Response to Nutrient Starvation. TOR Target of Ramamycin: Springer Berlin Heidelberg. pp. 73–84.

53. SinghR, KaushikS, WangY, XiangY, NovakI, et al. (2009) Autophagy regulates lipid metabolism. Nature 458: 1131–1135.

54. WelterE, ThummM, KrickR (2010) Quantification of nonselective bulk autophagy in S. cerevisiae using Pgk1-GFP. Autophagy 6: 794–797.

55. PanX, YeP, YuanDS, WangX, BaderJS, et al. (2006) A DNA integrity network in the yeast Sacchammyces cerevisiae. Cell 124: 1069–1081.

56. KlionskyDJ, EmrSD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290: 1717–1721.

57. KumaA, MizushimaN (2010) Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol 21: 683–690.

58. LevineB, KlionskyDJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Developmental cell 6: 463.

59. ManiR, St OngeRP, HartmanJL, GiaeverG, RothFP (2008) Defining genetic interaction. Proc Natl Acad Sci USA 105: 3461–3466.

60. SuzukiK, KubotaY, SekitoT, OhsumiY (2007) Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes to Cells 12: 209–218.

61. AricoS, PetiotA, BauvyC, DubbelhuisPF, MeijerAJ, et al. (2001) The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. Journal of Biological Chemistry 276: 35243–35246.

62. NairU, JotwaniA, GengJ, GammohN, RichersonD, et al. (2011) SNARE proteins are required for macroautophagy. Cell 146: 290–302.

63. YangZ, GengJ, YenWL, WangK, KlionskyDJ (2010) Positive or negative roles of different cyclin-dependent kinase Pho85-cyclin complexes orchestrate induction of autophagy in Saccharomyces cerevisiae. Molecular Cell 38: 250.

64. WangZ, WilsonWA, FujinoMA, RoachPJ (2001) Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog of AMP-Activated Protein Kinase, and the Cyclin-Dependent Kinase Pho85p. Molecular and Cellular Biology 21: 5742–5752.

65. GravesJA, HenrySA (2000) Regulation of the yeast INO1 gene: The products of the INO2, INO4 and OPI1 regulatory genes are not required for repression in response to inositol. Genetics 154: 1485–1495.

66. DasC, TylerJK (2012) Histone exchange and histone modifications during transcription and aging. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1819: 332–342.

67. KnaevelsrudH, SimonsenA (2012) Lipids in autophagy: constituents, signaling molecules and cargo with relevance to disease. Biochim Biophys Acta 1821: 1133–1145.

68. YamagataM, ObaraK, KiharaA (2011) Sphingolipid synthesis is involved in autophagy in Saccharomyces cerevisiae. Biochemical and Biophysical Research Communications 410: 786–791.

69. ShechtmanCF, HenneberryAL, SeimonTA, TinkelenbergAH, WilcoxLJ, et al. (2011) Loss of subcellular lipid transport due to ARV1 deficiency disrupts organelle homeostasis and activates the unfolded protein response. J Biol Chem 286: 11951–11959.

70. TongF, BillheimerJ, ShechtmanCF, LiuY, CrookeR, et al. (2010) Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism. Journal of Biological Chemistry 285: 33632–33641.

71. MaiS, MusterB, Bereiter-HahnJ, JendrachM (2012) Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy 8: 47–62.

72. HeymontJ, BerenfeldL, CollinsJ, KaganovichA, MaynesB, et al. (2000) TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation. Proc Natl Acad Sci USA 97: 12672–12677.

73. Ortega-MolinaA, EfeyanA, Lopez-GuadamillasE, Munoz-MartinM, Gomez-LopezG, et al. (2012) Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab 15: 382–394.

74. Di CristofanoA, De AcetisM, KoffA, Cordon-CardoC, PandolfiPP (2001) Pten and p27KIP1 cooperate in prostate cancer tumor suppression in the mouse. Nature Genetics 27: 222–224.

75. AllenC, ButtnerS, AragonAD, ThomasJA, MeirellesO, et al. (2006) Isolation of quiescent and nonquiescent cells from yeast stationary-phase cultures. J Cell Biol 174: 89–100.

76. KirkwoodTBL (2008) A systematic look at an old problem. Nature 451: 644–647.

77. TongA, BooneC (2006) Synthetic genetic array analysis in Saccharomyces cerevisiae. Methods in Molecular Biology (Clifton, NJ) 313: 171.

78. DeLunaA, VetsigianK, ShoreshN, HegrenessM, Colón-GonzálezM, et al. (2008) Exposing the fitness contribution of duplicated genes. Nature Genetics 40: 676–681.

79. QinH, LuM (2006) Natural variation in replicative and chronological life spans of Saccharomyces cerevisiae. Experimental Gerontology 41: 448.

80. SmootME, OnoK, RuscheinskiJ, WangP-L, IdekerT (2011) Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27: 431–432.