Advertisement

Biogerontology

, Volume 13, Issue 1, pp 21–35 | Cite as

Selective autophagy in the maintenance of cellular homeostasis in aging organisms

  • Vanessa M. Hubbard
  • Rut Valdor
  • Fernando Macian
  • Ana Maria Cuervo
Review Article

Abstract

Altered cellular homeostasis, accumulation of damaged non-functional organelles and presence of protein inclusions are characteristics shared by almost all types of differentiated cells in aged organisms. Cells rely on quality control mechanisms to prevent the occurrence of these events and the subsequent cellular compromise associated with them. What goes wrong in aging cells? Growing evidence supports gradual malfunctioning with age of the cellular quality control systems. In this review, we focus on autophagy, a catabolic process that contributes to the maintenance of cellular homeostasis through the degradation of unwanted and damaged components in lysosomes. We describe recent advances on the molecular characterization of this process, its different variants and the multiplicity of functions attributed to them. Autophagic dysfunction has been identified in severe human disorders, many of which worsen with age. We comment on the contribution of an adequate autophagic function to longevity, and the negative impact on health-span of the age-dependent decline in autophagic function.

Keywords

Aging Chaperones Health-span Longevity Lysosomes Neurodegeneration Proteotoxicity 

Notes

Acknowledgments

We thank the members of our groups for their constructive comments for this manuscript. Work in our laboratories is supported by NIH grants from NIA, NIAID, NIDKK, NINDS, a Glenn Foundation Award and a Hirsch/Weill-Caulier Career Scientist Award. V.M.H. is supported by F31AG035533.

References

  1. Agarraberes F, Dice JF (2001) A molecular chaperone complex at the lysosomal membrane is required for protein translocation. J Cell Sci 114:2491–2499PubMedGoogle Scholar
  2. Agarraberes F, Terlecky S et al (1997) An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol 137:825–834PubMedCrossRefGoogle Scholar
  3. Andrianjafiniony T, Dupre-Aucouturier S et al (2010) Oxidative stress, apoptosis, and proteolysis in skeletal muscle repair after unloading. Am J Physiol Cell Physiol 299:C307–C315PubMedCrossRefGoogle Scholar
  4. Aniento F, Roche E et al (1993) Uptake and degradation of glyceraldehyde-3-phosphate dehydrogenase by rat liver lysosomes. J Biol Chem 268:10463–10470PubMedGoogle Scholar
  5. Axe EL, Walker SA et al (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701PubMedCrossRefGoogle Scholar
  6. Bandyopadhyay U, Kaushik S et al (2008) The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. Mol Cell Biol 28:5747–5763PubMedCrossRefGoogle Scholar
  7. Bass TM, Weinkove D et al (2007) Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 128:546–552PubMedCrossRefGoogle Scholar
  8. Baur JA, Pearson KJ et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342PubMedCrossRefGoogle Scholar
  9. Bellu AR, Kiel JA (2003) Selective degradation of peroxisomes in yeasts. Microsc Res Tech 61:161–170PubMedCrossRefGoogle Scholar
  10. Bergamini E, Cavallini G et al (2003) The anti-ageing effects of caloric restriction may involve stimulation of macroautophagy and lysosomal degradation, and can be intensified pharmacologically. Biomed Pharmacother 53:203–208Google Scholar
  11. Bernales S, McDonald K et al (2006) Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4:e423PubMedCrossRefGoogle Scholar
  12. Bjorkoy G, Lamark T et al (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171:603–614PubMedCrossRefGoogle Scholar
  13. Broadley SA, Hartl FU (2009) The role of molecular chaperones in human misfolding diseases. FEBS Lett 583:2647–2653PubMedCrossRefGoogle Scholar
  14. Brunk UT, Terman A (2002) Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 33:611–619PubMedCrossRefGoogle Scholar
  15. Cavallini G, Donati A et al (2001) The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction. Exp Gerontol 36:497–506PubMedCrossRefGoogle Scholar
  16. Chen WH, Kozlovsky BF et al (2009) Vaccination in the elderly: an immunological perspective. Trends Immunol 30:351–359PubMedCrossRefGoogle Scholar
  17. Chiang H, Dice J (1988) Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem 263:6797–6803PubMedGoogle Scholar
  18. Chiang H, Terlecky S et al (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science 246:382–385PubMedCrossRefGoogle Scholar
  19. Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6:79–87PubMedCrossRefGoogle Scholar
  20. Cuervo AM (2004) Autophagy: many pathways to the same end. Mol Cell Biochem 263:55–72PubMedCrossRefGoogle Scholar
  21. Cuervo AM (2008) Autophagy and aging: keeping that old broom working. Trends Genet 24:604–612PubMedCrossRefGoogle Scholar
  22. Cuervo AM (2010a) Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol Metab 21:142–150PubMedCrossRefGoogle Scholar
  23. Cuervo AM (2010b) The plasma membrane brings autophagosomes to life. Nat Cell Biol 12:735–737PubMedCrossRefGoogle Scholar
  24. Cuervo AM, Dice JF (1996) A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273:501–503PubMedCrossRefGoogle Scholar
  25. Cuervo AM, Dice JF (2000a) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275:31505–31513PubMedCrossRefGoogle Scholar
  26. Cuervo AM, Dice JF (2000b) Regulation of lamp2a levels in the lysosomal membrane. Traffic 1:570–583PubMedCrossRefGoogle Scholar
  27. Cuervo AM, Dice JF (2000c) Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci 113:4441–4450PubMedGoogle Scholar
  28. Cuervo AM, Knecht E et al (1995a) Activation of a selective pathway of lysosomal proteolysis in rat liver by prolonged starvation. Am J Physiol 269:C1200–C1208PubMedGoogle Scholar
  29. Cuervo AM, Palmer A et al (1995b) Degradation of proteasomes by lysosomes in rat liver. Eur J Biochem 227:792–800PubMedCrossRefGoogle Scholar
  30. Cuervo AM, Dice JF et al (1997) A lysosomal population responsible for the hsc73-mediated degradation of cytosolic proteins in lysosomes. J Biol Chem 272:5606–5615PubMedCrossRefGoogle Scholar
  31. Cuervo AM, Hu W et al (1998) IkappaB is a substrate for a selective pathway of lysosomal proteolysis. Mol Biol Cell 9:1995–2010PubMedGoogle Scholar
  32. Cuervo AM, Hildebrand H et al (1999) Direct lysosomal uptake of alpha2-microglobulin contributes to chemically induced nephropathy. Kidney Int 55:529–545PubMedCrossRefGoogle Scholar
  33. Cuervo AM, Mann L et al (2003) Cathepsin A regulates chaperone-mediated autophagy through cleavage of the lysosomal receptor. EMBO J 22:12–19CrossRefGoogle Scholar
  34. Cuervo AM, Stefanis L et al (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRefGoogle Scholar
  35. Cullinane M, Gong L et al (2008) Stimulation of autophagy suppresses the intracellular survival of Burkholderia pseudomallei in mammalian cell lines. Autophagy 4:744–753PubMedGoogle Scholar
  36. De Duve C, Wattiaux R (1966) Functions of lysosomes [Review]. Ann Rev Physiol 28:435–492CrossRefGoogle Scholar
  37. Di Bartolomeo S, Nazio F et al (2010) The role of autophagy during development in higher eukaryotes. Traffic 11:1280–1289PubMedCrossRefGoogle Scholar
  38. Dice JF (1990) Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 15:305–309PubMedCrossRefGoogle Scholar
  39. Dice JF (2007) Chaperone-mediated autophagy. Autophagy 3:295–299PubMedGoogle Scholar
  40. Donati A, Cavallini G et al (2001) Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. J Gerontol A Biol Sci Med Sci 56:B288–B293PubMedCrossRefGoogle Scholar
  41. Eisenberg T, Knauer H et al (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11:1305–1314PubMedCrossRefGoogle Scholar
  42. English L, Chemali M et al (2009) Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection. Nat Immunol 10:480–487PubMedCrossRefGoogle Scholar
  43. Eskelinen EL, Cuervo AM et al (2005) Unifying nomenclature for the isoforms of the Lysosomal Membrane Protein LAMP-2. Traffic 6:1058–1061PubMedCrossRefGoogle Scholar
  44. Feldman DE, Frydman J (2000) Protein folding in vivo: the importance of molecular chaperones. Curr Opin Struct Biol 10:26–33PubMedCrossRefGoogle Scholar
  45. Ferdous A, Battiprolu PK et al (2010) FoxO, autophagy, and cardiac remodeling. J Cardiovasc Transl Res 3:355–364PubMedCrossRefGoogle Scholar
  46. Finn PF, Dice JF (2005) Ketone bodies stimulate chaperone-mediated autophagy. J Biol Chem 280:25864–25870PubMedCrossRefGoogle Scholar
  47. Franch HA, Sooparb S et al (2001) A mechanism regulating proteolysis of specific proteins during renal tubular cell growth. J Biol Chem 276:19126–19131PubMedCrossRefGoogle Scholar
  48. Fuertes G, Martin De Llano J et al (2003) Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid deprivation and confluent conditions. Biochem J 375:75–86PubMedCrossRefGoogle Scholar
  49. Geng J, Klionsky DJ (2010) The Golgi as a potential membrane source for autophagy. Autophagy 6:950–951PubMedCrossRefGoogle Scholar
  50. Goldberg AL (2003) Protein degradation and protection against misfolded or damaged proteins. Nature 18:895–899CrossRefGoogle Scholar
  51. Goldman SJ, Taylor R et al (2010) Autophagy and the degradation of mitochondria. Mitochondrion 10:309–315PubMedCrossRefGoogle Scholar
  52. Grubeck-Loebenstein B, Wick G (2002) The aging of the immune system. Adv Immunol 80:243–284PubMedCrossRefGoogle Scholar
  53. Gutierrez M, Master S et al (2004) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–766PubMedCrossRefGoogle Scholar
  54. Hailey DW, Rambold AS et al (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–667PubMedCrossRefGoogle Scholar
  55. Hansen M, Chandra A et al (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4:e24PubMedCrossRefGoogle Scholar
  56. Hara T, Nakamura K et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–889PubMedCrossRefGoogle Scholar
  57. Hayashi-Nishino M, Fujita N et al (2009) A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11:1433–1437PubMedCrossRefGoogle Scholar
  58. Hosokawa N, Hara T et al (2009) Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 20:1981–1991PubMedCrossRefGoogle Scholar
  59. Howitz KT, Bitterman KJ et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196PubMedCrossRefGoogle Scholar
  60. Hubbard VM, Valdor R et al (2010) Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol 185:7349–7357PubMedCrossRefGoogle Scholar
  61. Jia K, Levine B (2007) Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3:597–599PubMedGoogle Scholar
  62. Kabeya Y, Mizushima N et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19:5720–5728PubMedCrossRefGoogle Scholar
  63. Kabuta T, Wada K (2008) Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J Biol Chem 283:23731–23738PubMedCrossRefGoogle Scholar
  64. Kanki T, Klionsky DJ (2009) Atg32 is a tag for mitochondria degradation in yeast. Autophagy 5:1201–1202PubMedCrossRefGoogle Scholar
  65. Kaushik S, Massey AC et al (2006) Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy. EMBO J 25:3921–3933PubMedCrossRefGoogle Scholar
  66. Kaushik S, Singh R et al (2010) Autophagic pathways and metabolic stress. Diabetes Obes Metab 12:4–14PubMedCrossRefGoogle Scholar
  67. Kiffin R, Christian C et al (2004) Activation of chaperone-mediated autophagy during oxidative stress. Mol Biol Cell 15:4829–4840PubMedCrossRefGoogle Scholar
  68. Kiffin R, Kaushik S et al (2007) Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci 120:782–791PubMedCrossRefGoogle Scholar
  69. Kim I, Rodriguez-Enriquez S et al (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253PubMedCrossRefGoogle Scholar
  70. Kim PK, Hailey DW et al (2008) Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes. Proc Natl Acad Sci USA 105:20567–20574PubMedCrossRefGoogle Scholar
  71. Koga H, Kaushik S et al (2010a) Altered lipid content inhibits autophagic vesicular fusion. FASEB J 24:3052–3065PubMedCrossRefGoogle Scholar
  72. Koga H, Kaushik S et al (2010b) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10:205–215PubMedCrossRefGoogle Scholar
  73. Komatsu M, Ichimura Y (2010) Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 584:1374–1378PubMedCrossRefGoogle Scholar
  74. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169:425–434PubMedCrossRefGoogle Scholar
  75. Komatsu M, Waguri S et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–884PubMedCrossRefGoogle Scholar
  76. Kon M, Cuervo AM (2010) Chaperone-mediated autophagy in health and disease. FEBS Lett 584:1399–1404PubMedCrossRefGoogle Scholar
  77. Konecki DS, Foetisch K et al (1995) An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochem Biophys Res Commun 215:757–767PubMedCrossRefGoogle Scholar
  78. Kuma A, Hatano M et al (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036PubMedCrossRefGoogle Scholar
  79. Lamark T, Kirkin V et al (2009) NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8:1986–1990PubMedCrossRefGoogle Scholar
  80. Lee HK, Lund JM et al (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–1401PubMedCrossRefGoogle Scholar
  81. Lee IH, Cao L et al (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105:3374–3379PubMedCrossRefGoogle Scholar
  82. Lemasters J, Nieminen AL (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196PubMedCrossRefGoogle Scholar
  83. Levine B (2005) Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell 120:159–162PubMedGoogle Scholar
  84. Ling YM, Shaw MH et al (2006) Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages. J Exp Med 203:2063–2071PubMedCrossRefGoogle Scholar
  85. Liu H, Wang P et al (2009) Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. FASEB J 23:3383–3392PubMedCrossRefGoogle Scholar
  86. Lock R, Roy S et al (2010) Autophagy facilitates glycolysis during ras mediated oncogenic transformation. Mol Biol Cell 22:165–178PubMedCrossRefGoogle Scholar
  87. Mak SK, McCormack AL et al (2010) Lysosomal degradation of alpha-synuclein in vivo. J Biol Chem 285:13621–13629PubMedCrossRefGoogle Scholar
  88. Martinez-Vicente M, Sovak G et al (2005) Protein degradation and aging. Exp Gerontol 40:622–633PubMedCrossRefGoogle Scholar
  89. Martinez-Vicente M, Talloczy Z et al (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118:777–788PubMedGoogle Scholar
  90. Marzella L, Ahlberg J et al (1981) Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Arch B Cell Pathol 36:219–234CrossRefGoogle Scholar
  91. Massey AC, Kaushik S et al (2006) Consequences of the selective blockage of chaperone-mediated autophagy. Proc Nat Acad Sci USA 103:5905–5910CrossRefGoogle Scholar
  92. Mattoo H, Faulkner M et al (2009) Naive CD4 T cells from aged mice show enhanced death upon primary activation. Int Immunol 21:1277–1289PubMedCrossRefGoogle Scholar
  93. Mehrpour M, Esclatine A et al (2010) Overview of macroautophagy regulation in mammalian cells. Cell Res 20:748–762PubMedCrossRefGoogle Scholar
  94. Melendez A, Talloczy Z et al (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301:1387–1391PubMedCrossRefGoogle Scholar
  95. Mizushima N, Noda T et al (1998) A protein conjugation system essential for autophagy. Nature 395:395–398PubMedCrossRefGoogle Scholar
  96. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111PubMedCrossRefGoogle Scholar
  97. Mizushima N, Levine B et al (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedCrossRefGoogle Scholar
  98. Morimoto RI, Cuervo AM (2009) Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J Gerontol A Biol Sci Med Sci 64:167–170PubMedCrossRefGoogle Scholar
  99. Morselli E, Maiuri MC, et al. (2010). The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6Google Scholar
  100. Narendra D, Tanaka A et al (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803PubMedCrossRefGoogle Scholar
  101. Nedjic J, Aichinger M et al (2008) Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455:396–400PubMedCrossRefGoogle Scholar
  102. Orenstein SJ, Cuervo AM (2010) Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 21:719–726PubMedCrossRefGoogle Scholar
  103. Palotai R, Szalay MS et al (2008) Chaperones as integrators of cellular networks: changes of cellular integrity in stress and diseases. IUBMB Life 60:10–18PubMedCrossRefGoogle Scholar
  104. Pua HH, He YW (2007) Maintaining T lymphocyte homeostasis: another duty of autophagy. Autophagy 3:266–267PubMedGoogle Scholar
  105. Pua HH, Guo J et al (2009) Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol 182:4046–4055PubMedCrossRefGoogle Scholar
  106. Py BF, Lipinski MM et al (2007) Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy 3:117–125PubMedGoogle Scholar
  107. Qu XP, Yu J et al (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 112:1809–1820PubMedGoogle Scholar
  108. Rajagopal D, Bal V et al (2006) A role for the Hsp90 molecular chaperone family in antigen presentation to T lymphocytes via major histocompatibility complex class II molecules. Eur J Immunol 36:828–841PubMedCrossRefGoogle Scholar
  109. Ravikumar B, Rubinsztein DC (2004) Can autophagy protect against neurodegeneration caused by aggregate-prone proteins? Neuroreport 15:2443–2445PubMedCrossRefGoogle Scholar
  110. Ravikumar B, Vacher C et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595PubMedCrossRefGoogle Scholar
  111. Ravikumar B, Moreau K et al (2010a) Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 12:747–757PubMedCrossRefGoogle Scholar
  112. Ravikumar B, Sarkar S et al (2010b) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435PubMedCrossRefGoogle Scholar
  113. Sahu R, Kaushik S et al (2011) Microautohagy of cytosolic proteins by late endosomes. Dev Cell (Epub ahead of print)Google Scholar
  114. Salminen A, Kaarniranta K (2009) SIRT1: regulation of longevity via autophagy. Cell Signal 21:1356–1360PubMedCrossRefGoogle Scholar
  115. Sanjuan MA, Dillon CP et al (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450:1253–1257PubMedCrossRefGoogle Scholar
  116. Scarlatti F, Maffei R et al (2008) Role of non-canonical Beclin 1-independent autophagy in cell death induced by resveratrol in human breast cancer cells. Cell Death Differ 15:1318–1329PubMedCrossRefGoogle Scholar
  117. Simonsen A, Birkeland HC et al (2004) Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes. J Cell Sci 117:4239–4251PubMedCrossRefGoogle Scholar
  118. Singh R, Kaushik S et al (2009a) Autophagy regulates lipid metabolism. Nature 458:1131–1135PubMedCrossRefGoogle Scholar
  119. Singh R, Xiang Y et al (2009b) Autophagy regulates adipose mass and differentiation in mice. J Clin Invest 119:3329–3339PubMedCrossRefGoogle Scholar
  120. Sooparb S, Price SR et al (2004) Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus. Kidney Int 65:2135–2144PubMedCrossRefGoogle Scholar
  121. Vittorini S, Paradiso C et al (1999) The age-related accumulation of protein carbonyl in rat liver correlates with the age-related decline in liver proteolytic activities. J Gerontol 54:B318–B323Google Scholar
  122. Wang RC, Levine B (2010) Autophagy in cellular growth control. FEBS Lett 584:1417–1426PubMedCrossRefGoogle Scholar
  123. Wang Y, Martinez-Vicente M et al (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170PubMedCrossRefGoogle Scholar
  124. Ward W (2002) Protein degradation in the aging organism. Prog Mol Subcell Biol 29:35–42PubMedCrossRefGoogle Scholar
  125. Waters S, Marchbank K et al (2009) Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic protein turnover. FEBS Lett 583:1846–1852PubMedCrossRefGoogle Scholar
  126. Waters S, Marchbank K et al (2010) Autophagic receptors Nbr1 and p62 coregulate skeletal remodeling. Autophagy 6:981–983PubMedCrossRefGoogle Scholar
  127. Wing S, Chiang HL et al (1991) Proteins containing peptide sequences related to KFERQ are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J 275:165–169PubMedGoogle Scholar
  128. Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13:805–811PubMedCrossRefGoogle Scholar
  129. Xilouri M, Vogiatzi T et al (2009) Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One 4:e5515PubMedCrossRefGoogle Scholar
  130. Xu Y, Jagannath C et al (2007) Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity 27:135–144PubMedCrossRefGoogle Scholar
  131. Yang Z, Klionsky DJ (2010a) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822PubMedCrossRefGoogle Scholar
  132. Yang Z, Klionsky DJ (2010b) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131PubMedCrossRefGoogle Scholar
  133. Yang Q, She H et al (2009) Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy. Science 323:124–127PubMedCrossRefGoogle Scholar
  134. Yang DS, Stavrides P et al (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain 134:258–277PubMedCrossRefGoogle Scholar
  135. Yen WL, Shintani T et al (2010) The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J Cell Biol 188:101–114PubMedCrossRefGoogle Scholar
  136. Yorimitsu T, Klionsky DJ (2007) Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol 17:279–285PubMedCrossRefGoogle Scholar
  137. Yue Z, Jin S, Yang C, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100:15077–15082PubMedCrossRefGoogle Scholar
  138. Zhang C, Cuervo AM (2008) Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14:959–965PubMedCrossRefGoogle Scholar
  139. Zhou D, Li P et al (2005) Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. Immunity 22:571–581PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Vanessa M. Hubbard
    • 1
  • Rut Valdor
    • 1
  • Fernando Macian
    • 1
    • 3
  • Ana Maria Cuervo
    • 2
    • 3
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Developmental and Molecular BiologyAlbert Einstein College of MedicineBronxUSA
  3. 3.Institute for Aging ResearchAlbert Einstein College of MedicineBronxUSA

Personalised recommendations