Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1

English version České info

Advanced cellular age is associated with decreased efficiency of the proteostasis network. The proteasome, a protease in the cytoplasm and nuclei of eukaryotic cells, is an important component of this network. Recent studies demonstrate that increased proteasome capacity has a positive impact on longevity. The underlying mechanisms, however, have not been fully identified. Here we report that proteasomes are involved in regulating the AMP-activated kinase (AMPK) pathway and thus participate in correct metabolic adaptation. We find that Mig1, a transcriptional repressor downstream of yeast AMPK, Snf1, is a proteasome target and a negative regulator of lifespan. Increased proteasome activity results in enhanced turnover and incorrect localization of Mig1. The reduced Mig1 levels result in the induction of respiration and upregulation of the oxidative stress response. Premature Mig1 inactivation is also observed in two additional long-lived strains that overexpress SIR2 or are deleted for HXK2 and lifespan extension in both strains requires correct proteasome function. Our results uncover an interconnected network comprised of the proteasome, Sir2 and AMPK/Hxk2 signaling that impacts longevity through regulation of Mig1 and modulates respiratory metabolism. Mechanistic information on the cross-communication between these pathways is expected to facilitate the identification of novel pro-aging interventions.

Vyšlo v časopise: Proteasomes, Sir2, and Hxk2 Form an Interconnected Aging Network That Impinges on the AMPK/Snf1-Regulated Transcriptional Repressor Mig1. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004968
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004968

Souhrn

Zdroje

1. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, et al. (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6: 280–293. doi: 10.1016/j.cmet.2007.08.011 17908557

2. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, et al. (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418: 344–348. doi: 10.1038/nature00829 12124627

3. Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, et al. (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103: 1768–1773. doi: 10.1073/pnas.0510452103 16446459

4. Yang W, Hekimi S (2010) A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 8: e1000556. doi: 10.1371/journal.pbio.1000556 21151885

5. Andziak B, O’Connor TP, Qi W, DeWaal EM, Pierce A, et al. (2006) High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging cell 5: 463–471. doi: 10.1111/j.1474-9726.2006.00237.x 17054663

6. Pan Y, Schroeder EA, Ocampo A, Barrientos A, Shadel GS (2011) Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell Metab 13: 668–678. doi: 10.1016/j.cmet.2011.03.018 21641548

7. Ocampo A, Liu J, Schroeder EA, Shadel GS, Barrientos A (2012) Mitochondrial respiratory thresholds regulate yeast chronological life span and its extension by caloric restriction. Cell Metab 16: 55–67. doi: 10.1016/j.cmet.2012.05.013 22768839

8. Markaki M, Tavernarakis N (2013) Metabolic control by target of rapamycin and autophagy during ageing—a mini-review. Gerontology 59: 340–348. doi: 10.1159/000348599 23594965

9. Kaeberlein M (2010) Resveratrol and rapamycin: are they anti-aging drugs? Bioessays 32: 96–99. doi: 10.1002/bies.200900171 20091754

10. Hughes KJ, Kennedy BK (2012) Cell biology. Rapamycin paradox resolved. Science 335: 1578–1579. doi: 10.1126/science.1221365 22461595

11. Kennedy BK, Pennypacker JK (2014) Drugs that modulate aging: the promising yet difficult path ahead. Translational research: the journal of laboratory and clinical medicine 163: 456–465. doi: 10.1016/j.trsl.2013.11.007

12. Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annual review of pharmacology and toxicology 52: 381–400. doi: 10.1146/annurev-pharmtox-010611-134537 22017684

13. Jager S, Handschin C, St-Pierre J, Spiegelman BM (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 104: 12017–12022. doi: 10.1073/pnas.0705070104 17609368

14. Fendt SM, Sauer U (2010) Transcriptional regulation of respiration in yeast metabolizing differently repressive carbon substrates. BMC Syst Biol 4: 12. doi: 10.1186/1752-0509-4-12 20167065

15. Egan D, Kim J, Shaw RJ, Guan KL (2011) The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7: 643–644. doi: 10.4161/auto.7.6.15123 21460621

16. Usaite R, Jewett MC, Oliveira AP, Yates JR 3rd, Olsson L, et al. (2009) Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator. Molecular systems biology 5: 319. doi: 10.1038/msb.2009.67 19888214

17. Canto C, Auwerx J (2011) Calorie restriction: is AMPK a key sensor and effector? Physiology 26: 214–224. doi: 10.1152/physiol.00010.2011 21841070

18. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, et al. (2013) Metformin improves healthspan and lifespan in mice. Nature communications 4: 2192. doi: 10.1038/ncomms3192 23900241

19. Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes & development 18: 3004–3009. doi: 10.1101/gad.1255404

20. Tohyama D, Yamaguchi A (2010) A critical role of SNF1A/dAMPKalpha (Drosophila AMP-activated protein kinase alpha) in muscle on longevity and stress resistance in Drosophila melanogaster. Biochem Biophys Res Commun 394: 112–118. doi: 10.1016/j.bbrc.2010.02.126 20184862

21. Ashrafi K, Lin SS, Manchester JK, Gordon JI (2000) Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes & development 14: 1872–1885.

22. Lorenz DR, Cantor CR, Collins JJ (2009) A network biology approach to aging in yeast. Proc Natl Acad Sci U S A 106: 1145–1150. doi: 10.1073/pnas.0812551106 19164565

23. Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annual review of biochemistry 78: 477–513. doi: 10.1146/annurev.biochem.78.081507.101607 19489727

24. Kruegel U, Robison B, Dange T, Kahlert G, Delaney JR, et al. (2011) Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae. PLoS genetics 7: e1002253. doi: 10.1371/journal.pgen.1002253 21931558

25. Vilchez D, Morantte I, Liu Z, Douglas PM, Merkwirth C, et al. (2012) RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489: 263–268. doi: 10.1038/nature11315 22922647

26. Tonoki A, Kuranaga E, Tomioka T, Hamazaki J, Murata S, et al. (2009) Genetic evidence linking age-dependent attenuation of the 26S proteasome with the aging process. Mol Cell Biol 29: 1095–1106. doi: 10.1128/MCB.01227-08 19075009

27. Chondrogianni N, Petropoulos I, Franceschi C, Friguet B, Gonos ES (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Experimental gerontology 35: 721–728. doi: 10.1016/S0531-5565(00)00137-6 11053662

28. Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, et al. (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A 106: 3059–3064. doi: 10.1073/pnas.0809620106 19223593

29. Salmon AB, Leonard S, Masamsetti V, Pierce A, Podlutsky AJ, et al. (2009) The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis. FASEB J 23: 2317–2326. doi: 10.1096/fj.08-122523 19244163

30. Andersson V, Hanzen S, Liu B, Molin M, Nystrom T (2013) Enhancing protein disaggregation restores proteasome activity in aged cells. Aging 5: 802–812. 24243762

31. Geng F, Wenzel S, Tansey WP (2012) Ubiquitin and proteasomes in transcription. Annu Rev Biochem 81: 177–201. doi: 10.1146/annurev-biochem-052110-120012 22404630

32. Xie Y, Varshavsky A (2001) RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: a negative feedback circuit. Proc Natl Acad Sci U S A 98: 3056–3061. doi: 10.1073/pnas.071022298 11248031

33. Taylor EB, Rutter J (2011) Mitochondrial quality control by the ubiquitin-proteasome system. Biochem Soc Trans 39: 1509–1513. doi: 10.1042/BST0391509 21936843

34. Cohen MM, Leboucher GP, Livnat-Levanon N, Glickman MH, Weissman AM (2008) Ubiquitin-proteasome-dependent degradation of a mitofusin, a critical regulator of mitochondrial fusion. Molecular biology of the cell 19: 2457–2464. doi: 10.1091/mbc.E08-02-0227 18353967

35. Escobar-Henriques M, Westermann B, Langer T (2006) Regulation of mitochondrial fusion by the F-box protein Mdm30 involves proteasome-independent turnover of Fzo1. The Journal of cell biology 173: 645–650. doi: 10.1083/jcb.200512079 16735578

36. Leboucher GP, Tsai YC, Yang M, Shaw KC, Zhou M, et al. (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell 47: 547–557. doi: 10.1016/j.molcel.2012.05.041 22748923

37. Tar K, Dange T, Yang C, Yao Y, Bulteau AL, et al. (2014) Proteasomes Associated with the Blm10 Activator Protein Antagonize Mitochondrial Fission through Degradation of the Fission Protein Dnm1. J Biol Chem 289: 12145–12156. doi: 10.1074/jbc.M114.554105 24604417

38. Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT, et al. (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol 143: 359–373. doi: 10.1083/jcb.143.2.359 9786948

39. Westermann B (2012) Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta 1817: 1833–1838. doi: 10.1016/j.bbabio.2012.02.033 22409868

40. Horan MP, Pichaud N, Ballard JW (2012) Review: quantifying mitochondrial dysfunction in complex diseases of aging. The journals of gerontology Series A, Biological sciences and medical sciences 67: 1022–1035. doi: 10.1093/gerona/glr263 22459622

41. Dejean L, Beauvoit B, Guerin B, Rigoulet M (2000) Growth of the yeast Saccharomyces cerevisiae on a non-fermentable substrate: control of energetic yield by the amount of mitochondria. Biochim Biophys Acta 1457: 45–56. doi: 10.1016/S0005-2728(00)00053-0 10692549

42. Sadeh A, Movshovich N, Volokh M, Gheber L, Aharoni A (2011) Fine-tuning of the Msn2/4-mediated yeast stress responses as revealed by systematic deletion of Msn2/4 partners. Mol Biol Cell 22: 3127–3138. doi: 10.1091/mbc.E10-12-1007 21757539

43. Hedbacker K, Carlson M (2008) SNF1/AMPK pathways in yeast. Front Biosci 13: 2408–2420. doi: 10.2741/2854 17981722

44. Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 11: 230–241. doi: 10.1016/j.arr.2011.12.005 22186033

45. Vincent O, Townley R, Kuchin S, Carlson M (2001) Subcellular localization of the Snf1 kinase is regulated by specific beta subunits and a novel glucose signaling mechanism. Genes & development 15: 1104–1114. doi: 10.1101/gad.879301

46. Schmidt MC, McCartney RR (2000) beta-subunits of Snf1 kinase are required for kinase function and substrate definition. EMBO J 19: 4936–4943. doi: 10.1093/emboj/19.18.4936 10990457

47. Zaman S, Lippman SI, Zhao X, Broach JR (2008) How Saccharomyces responds to nutrients. Annual review of genetics 42: 27–81. doi: 10.1146/annurev.genet.41.110306.130206 18303986

48. Westholm JO, Nordberg N, Muren E, Ameur A, Komorowski J, et al. (2008) Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig3. BMC genomics 9: 601. doi: 10.1186/1471-2164-9-601 19087243

49. Nehlin JO, Ronne H (1990) Yeast MIG1 repressor is related to the mammalian early growth response and Wilms’ tumour finger proteins. EMBO J 9: 2891–2898. 2167835

50. Westergaard SL, Oliveira AP, Bro C, Olsson L, Nielsen J (2007) A systems biology approach to study glucose repression in the yeast Saccharomyces cerevisiae. Biotechnol Bioeng 96: 134–145. doi: 10.1002/bit.21135 16878332

51. Ahuatzi D, Riera A, Pelaez R, Herrero P, Moreno F (2007) Hxk2 regulates the phosphorylation state of Mig1 and therefore its nucleocytoplasmic distribution. J Biol Chem 282: 4485–4493. doi: 10.1074/jbc.M606854200 17178716

52. Harkness TA, Shea KA, Legrand C, Brahmania M, Davies GF (2004) A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast. Genetics 168: 759–774. doi: 10.1534/genetics.104.027771 15514051

53. Fernandez-Cid A, Riera A, Herrero P, Moreno F (2012) Glucose levels regulate the nucleo-mitochondrial distribution of Mig2. Mitochondrion 12: 370–380. doi: 10.1016/j.mito.2012.02.001 22353369

54. Moreno F, Ahuatzi D, Riera A, Palomino CA, Herrero P (2005) Glucose sensing through the Hxk2-dependent signalling pathway. Biochem Soc Trans 33: 265–268. doi: 10.1042/BST0330265 15667322

55. Schuurmans JM, Rossell SL, van Tuijl A, Bakker BM, Hellingwerf KJ, et al. (2008) Effect of hxk2 deletion and HAP4 overexpression on fermentative capacity in Saccharomyces cerevisiae. FEMS yeast research 8: 195–203. doi: 10.1111/j.1567-1364.2007.00319.x 18179578

56. Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & development 13: 2570–2580. doi: 10.1101/gad.13.19.2570

57. Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283: 27628–27635. doi: 10.1074/jbc.M805711200 18687677

58. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056–1060. doi: 10.1038/nature07813 19262508

59. Wang Y, Liang Y, Vanhoutte PM (2011) SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett 585: 986–994. doi: 10.1016/j.febslet.2010.11.047 21130086

60. Baraibar MA, Friguet B (2012) Changes of the proteasomal system during the aging process. Prog Mol Biol Transl Sci 109: 249–275. doi: 10.1016/B978-0-12-397863-9.00007-9 22727424

61. Segref A, Kevei E, Pokrzywa W, Schmeisser K, Mansfeld J, et al. (2014) Pathogenesis of human mitochondrial diseases is modulated by reduced activity of the ubiquitin/proteasome system. Cell Metab 19: 642–652. doi: 10.1016/j.cmet.2014.01.016 24703696

62. Fukui H, Moraes CT (2007) Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. Hum Mol Genet 16: 783–797. doi: 10.1093/hmg/ddm023 17356014

63. Livnat-Levanon N, Kevei E, Kleifeld O, Krutauz D, Segref A, et al. (2014) Reversible 26S Proteasome Disassembly upon Mitochondrial Stress. Cell reports 7: 1371–1380. doi: 10.1016/j.celrep.2014.04.030 24857655

64. Wang X, Yen J, Kaiser P, Huang L (2010) Regulation of the 26S proteasome complex during oxidative stress. Sci Signal 3: ra88. doi: 10.1126/scisignal.2001232 21139140

65. Sullivan PG, Dragicevic NB, Deng JH, Bai Y, Dimayuga E, et al. (2004) Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover. J Biol Chem 279: 20699–20707. doi: 10.1074/jbc.M313579200 14742431

66. Tsakiri EN, Sykiotis GP, Papassideri IS, Terpos E, Dimopoulos MA, et al. (2013) Proteasome dysfunction in Drosophila signals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging. Aging cell 12: 802–813. doi: 10.1111/acel.12111 23738891

67. Malc E, Dzierzbicki P, Kaniak A, Skoneczna A, Ciesla Z (2009) Inactivation of the 20S proteasome maturase, Ump1p, leads to the instability of mtDNA in Saccharomyces cerevisiae. Mutation research 669: 95–103. doi: 10.1016/j.mrfmmm.2009.05.008 19467248

68. Lin SS, Manchester JK, Gordon JI (2003) Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in Saccharomyces cerevisiae by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem 278: 13390–13397. doi: 10.1074/jbc.M212818200 12562756

69. Marino G, Ugalde AP, Salvador-Montoliu N, Varela I, Quiros PM, et al. (2008) Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum Mol Genet 17: 2196–2211. doi: 10.1093/hmg/ddn120 18443001

70. Delaney JR, Murakami C, Chou A, Carr D, Schleit J, et al. (2013) Dietary restriction and mitochondrial function link replicative and chronological aging in Saccharomyces cerevisiae. Experimental gerontology 48: 1006–1013. doi: 10.1016/j.exger.2012.12.001 23235143

71. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK (2005) Genes determining yeast replicative life span in a long-lived genetic background. Mech Ageing Dev 126: 491–504. doi: 10.1016/j.mad.2004.10.007 15722108

72. Rolland F, Winderickx J, Thevelein JM (2002) Glucose-sensing and -signalling mechanisms in yeast. FEMS yeast research 2: 183–201. doi: 10.1016/S1567-1356(02)00046-6 12702307

73. Finley LW, Haigis MC (2009) The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Ageing Res Rev 8: 173–188. doi: 10.1016/j.arr.2009.03.003 19491041

74. Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800. doi: 10.1038/35001622 10693811

75. Brachmann CB, Davies A, Cost GJ, Caputo E, Li J, 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. doi: 10.1002/(SICI)1097-0061(19980130)14:2%3C115::AID-YEA204%3E3.0.CO;2-2 9483801

76. Horecka J, Davis RW (2014) The 50:50 method for PCR-based seamless genome editing in yeast. Yeast 31: 103–112. doi: 10.1002/yea.2992 24639370

77. Sesaki H, Jensen RE (1999) Division versus fusion: Dnm1p and Fzo1p antagonistically regulate mitochondrial shape. J Cell Biol 147: 699–706. doi: 10.1083/jcb.147.4.699 10562274

78. Naylor K, Ingerman E, Okreglak V, Marino M, Hinshaw JE, et al. (2006) Mdv1 interacts with assembled dnm1 to promote mitochondrial division. J Biol Chem 281: 2177–2183. doi: 10.1074/jbc.M507943200 16272155

79. Kushnirov VV (2000) Rapid and reliable protein extraction from yeast. Yeast 16: 857–860. doi: 10.1002/1097-0061(20000630)16:9%3C857::AID-YEA561%3E3.0.CO;2-B 10861908

80. Collins GA, Gomez TA, Deshaies RJ, Tansey WP (2010) Combined chemical and genetic approach to inhibit proteolysis by the proteasome. Yeast 27: 965–974. doi: 10.1002/yea.1805 20625982