Autophagy: molecular mechanisms, physiological functions and relevance in human pathology

Autophagy is a degradative mechanism mainly involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. Over the last years, yeast genetic screens have considerably increased our knowledge about the molecular mechanisms of autophagy, and a number of genes involved in fundamental steps of the autophagic pathway have been identified. Most of these autophagy genes are present in higher eukaryotes indicating that this process has been evolutionarily conserved. In yeast, autophagy is mainly involved in adaptation to starvation, but in multicellular organisms this route has emerged as a multifunctional pathway involved in a variety of additional processes such as programmed cell death, removal of damaged organelles and development of different tissue-specific functions. Furthermore, autophagy is associated with a growing number of pathological conditions, including cancer, myopathies and neurodegenerative disorders. The physiological and pathological roles of autophagy, as well as the molecular mechanisms underlying this multifunctional pathway, are discussed in this review.

[1]  A. Yamamoto,et al.  SKD1 AAA ATPase-dependent endosomal transport is involved in autolysosome formation. , 2002, Cell structure and function.

[2]  P. Clarke,et al.  Developmental cell death: morphological diversity and multiple mechanisms , 2004, Anatomy and Embryology.

[3]  Nektarios Tavernarakis,et al.  Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos? , 2002, EMBO reports.

[4]  V. Lelyveld,et al.  A Single Protease, Apg4B, Is Specific for the Autophagy-related Ubiquitin-like Proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L* , 2003, Journal of Biological Chemistry.

[5]  H. Merker,et al.  The morphology of various types of cell death in prenatal tissues. , 1973, Teratology.

[6]  James R. Knight,et al.  A comprehensive analysis of protein–protein interactions in Saccharomyces cerevisiae , 2000, Nature.

[7]  C. Duve,et al.  Functions of lysosomes. , 1966, Annual review of physiology.

[8]  Takeshi Noda,et al.  Apg2p Functions in Autophagosome Formation on the Perivacuolar Structure* , 2001, The Journal of Biological Chemistry.

[9]  Jeremy N. Skepper,et al.  α-Synuclein Is Degraded by Both Autophagy and the Proteasome* , 2003, Journal of Biological Chemistry.

[10]  Jun O. Liu,et al.  Post-translational Modifications of Three Members of the Human MAP1LC3 Family and Detection of a Novel Type of Modification for MAP1LC3B* , 2003, Journal of Biological Chemistry.

[11]  P. Dean,et al.  X‐Linked myopathy with excessive autophagy: A new hereditary muscle disease , 1988, Annals of neurology.

[12]  E. Knecht,et al.  Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. , 2000, The Journal of biological chemistry.

[13]  M. Matsui,et al.  In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. , 2003, Molecular biology of the cell.

[14]  D. Attaix,et al.  Class III phosphoinositide 3-kinase--Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. , 2003, The Biochemical journal.

[15]  P. Stahl,et al.  Rab22a affects the morphology and function of the endocytic pathway. , 2001, Journal of cell science.

[16]  Y. Bailly,et al.  Lurcher GRID2-Induced Death and Depolarization Can Be Dissociated in Cerebellar Purkinje Cells , 2003, Neuron.

[17]  E. Bergamini,et al.  Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis , 2003, Experimental Gerontology.

[18]  R. Nixon,et al.  Lysosomal abnormalities in degenerating neurons link neuronal compromise to senile plaque development in Alzheimer disease , 1994, Brain Research.

[19]  K. Kirkegaard,et al.  Remodeling the Endoplasmic Reticulum by Poliovirus Infection and by Individual Viral Proteins: an Autophagy-Like Origin for Virus-Induced Vesicles , 2000, Journal of Virology.

[20]  Y. Agid,et al.  Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. , 1997, Histology and histopathology.

[21]  Takeshi Noda,et al.  Yeast autophagosomes: de novo formation of a membrane structure. , 2002, Trends in cell biology.

[22]  R. Flavell,et al.  A Salmonella protein causes macrophage cell death by inducing autophagy , 2003, The Journal of cell biology.

[23]  T. Natsume,et al.  Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate , 2003, Journal of Cell Science.

[24]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[25]  L. Thompson,et al.  Autophagy regulates the processing of amino terminal huntingtin fragments. , 2003, Human molecular genetics.

[26]  S. Emr,et al.  Phosphoinositide 3-Kinases and Their FYVE Domain-containing Effectors as Regulators of Vacuolar/Lysosomal Membrane Trafficking Pathways* , 1999, The Journal of Biological Chemistry.

[27]  G. Kroemer,et al.  Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells , 2000, Cell Death and Differentiation.

[28]  A. Mayer,et al.  Docking of Yeast Vacuoles Is Catalyzed by the Ras-like GTPase Ypt7p after Symmetric Priming by Sec18p (NSF) , 1997, The Journal of cell biology.

[29]  W. Bradford,et al.  Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. , 1976, The American journal of pathology.

[30]  A Kihara,et al.  Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. , 2001, Molecular biology of the cell.

[31]  Rainer Duden,et al.  Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. , 2002, Human molecular genetics.

[32]  Chao Zhang,et al.  Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. , 2003, Molecular biology of the cell.

[33]  P. Seglen,et al.  Ultrastructural and immunocytochemical characterization of autophagic vacuoles in isolated hepatocytes: effects of vinblastine and asparagine on vacuole distributions. , 1995, Experimental cell research.

[34]  P. Seglen,et al.  Inhibition of autophagic-lysosomal delivery and autophagic lactolysis by asparagine , 1991, The Journal of cell biology.

[35]  Daniel J Klionsky,et al.  A unified nomenclature for yeast autophagy-related genes. , 2003, Developmental cell.

[36]  J. Slot,et al.  The Autophagic and Endocytic Pathways Converge at the Nascent Autophagic Vacuoles , 1997, The Journal of cell biology.

[37]  C. López-Otín,et al.  Molecular Cloning and Structural and Functional Characterization of Human Cathepsin F, a New Cysteine Proteinase of the Papain Family with a Long Propeptide Domain* , 1999, The Journal of Biological Chemistry.

[38]  J. Teckman,et al.  Mitochondrial Autophagy and Injury in the Liver in Alpha-1-antitrypsin Deficiency , 2022 .

[39]  M. Colombo,et al.  Induction of Autophagy Causes Dramatic Changes in the Subcellular Distribution of GFP‐Rab24 , 2002, Traffic.

[40]  D. Klionsky,et al.  Apg2 Is a Novel Protein Required for the Cytoplasm to Vacuole Targeting, Autophagy, and Pexophagy Pathways* , 2001, The Journal of Biological Chemistry.

[41]  J. Dennis,et al.  Biogenesis of multilamellar bodies via autophagy. , 2000, Molecular biology of the cell.

[42]  A. Progulske-Fox,et al.  Bacterial interactions with the autophagic pathway , 2002, Cellular microbiology.

[43]  M. Schlumpberger,et al.  AUT1, a gene essential for autophagocytosis in the yeast Saccharomyces cerevisiae , 1997, Journal of bacteriology.

[44]  C. Eng,et al.  PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. , 1999, Cancer research.

[45]  D. Klionsky,et al.  Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. , 2002, Developmental cell.

[46]  Eric Ogier-Denis,et al.  Autophagy: a barrier or an adaptive response to cancer. , 2003, Biochimica et biophysica acta.

[47]  E. Kominami,et al.  Autophagy in embryonic erythroid cells: its role in maturation. , 2000, European journal of cell biology.

[48]  Takeshi Noda,et al.  Formation Process of Autophagosome Is Traced with Apg8/Aut7p in Yeast , 1999, The Journal of cell biology.

[49]  Takeshi Noda,et al.  Apg16p is required for the function of the Apg12p–Apg5p conjugate in the yeast autophagy pathway , 1999, The EMBO journal.

[50]  Raeka S. Aiyar,et al.  Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy , 2002, Neurology.

[51]  D. Klionsky,et al.  Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. , 2001, Molecular biology of the cell.

[52]  D. Klionsky,et al.  Vacuolar import of proteins and organelles from the cytoplasm. , 1999, Annual review of cell and developmental biology.

[53]  D. Klionsky,et al.  Molecular machinery required for autophagy and the cytoplasm to vacuole targeting (Cvt) pathway in S. cerevisiae. , 2002, Current opinion in cell biology.

[54]  Takeshi Noda,et al.  Two Distinct Vps34 Phosphatidylinositol 3–Kinase Complexes Function in Autophagy and Carboxypeptidase Y Sorting inSaccharomyces cerevisiae , 2001, The Journal of cell biology.

[55]  James E. Goldman,et al.  Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein , 1998, Journal of Virology.

[56]  A. Cuervo,et al.  How do intracellular proteolytic systems change with age? , 1998, Frontiers in bioscience : a journal and virtual library.

[57]  A. Meijer,et al.  Turnover of peroxisomal vesicles by autophagic proteolysis in cultured fibroblasts from Zellweger patients. , 1992, European journal of cell biology.

[58]  K. Kato,et al.  Immunocytochemical study of the surrounding envelope of autophagic vacuoles in cultured rat hepatocytes. , 1990, Experimental cell research.

[59]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[60]  R. Lüllmann-Rauch,et al.  Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice , 2000, Nature.

[61]  J. Eaton,et al.  Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis , 2003, Experimental Gerontology.

[62]  N. Heintz,et al.  A Novel Protein Complex Linking the δ2 Glutamate Receptor and Autophagy Implications for Neurodegeneration in Lurcher Mice , 2002, Neuron.

[63]  M. Swanson,et al.  A Microbial Strategy to Multiply in Macrophages: The Pregnant Pause , 2002, Traffic.

[64]  T. Nemoto,et al.  Mammalian Apg12p, but not the Apg12p.Apg5p conjugate, facilitates LC3 processing. , 2002, Biochemical and biophysical research communications.

[65]  T. Yoshimori Autophagy: a regulated bulk degradation process inside cells. , 2004, Biochemical and biophysical research communications.

[66]  D. Klionsky,et al.  Membrane Recruitment of Aut7p in the Autophagy and Cytoplasm to Vacuole Targeting Pathways Requires Aut1p, Aut2p, and the Autophagy Conjugation Complex , 2001, The Journal of cell biology.

[67]  S. Stellar,et al.  Electron microscope and enzyme studies in cerebral biopsies of Huntington's chorea. , 1974, Transactions of the American Neurological Association.

[68]  D. Klionsky,et al.  Convergence of Multiple Autophagy and Cytoplasm to Vacuole Targeting Components to a Perivacuolar Membrane Compartment Prior tode Novo Vesicle Formation* , 2002, The Journal of Biological Chemistry.

[69]  S. Arico,et al.  The Tumor Suppressor PTEN Positively Regulates Macroautophagy by Inhibiting the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway* , 2001, The Journal of Biological Chemistry.

[70]  S. Dimauro,et al.  Lysosomal glycogen storage disease with normal acid maltase , 1981, Neurology.

[71]  Takeshi Noda,et al.  The Reversible Modification Regulates the Membrane-Binding State of Apg8/Aut7 Essential for Autophagy and the Cytoplasm to Vacuole Targeting Pathway , 2000, The Journal of cell biology.

[72]  Arnold J. Levine,et al.  Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[73]  D. Tindall,et al.  Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor γ ligand, 15-deoxy-Δ12,14-prostaglandin J2 , 2000 .

[74]  A. Gingras,et al.  The target of rapamycin (TOR) proteins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[75]  Takeshi Tokuhisa,et al.  Dissection of Autophagosome Formation Using Apg5-Deficient Mouse Embryonic Stem Cells , 2001, The Journal of cell biology.

[76]  D. Tindall,et al.  Nonapoptotic cell death associated with S-phase arrest of prostate cancer cells via the peroxisome proliferator-activated receptor gamma ligand, 15-deoxy-delta12,14-prostaglandin J2. , 2000, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[77]  A. D. de Grey A proposed refinement of the mitochondrial free radical theory of aging. , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[78]  P. Codogno,et al.  Distinct Classes of Phosphatidylinositol 3′-Kinases Are Involved in Signaling Pathways That Control Macroautophagy in HT-29 Cells* , 2000, The Journal of Biological Chemistry.

[79]  Takeshi Noda,et al.  A ubiquitin-like system mediates protein lipidation , 2000, Nature.

[80]  I. Nishino Autophagic vacuolar myopathies , 2003, Current neurology and neuroscience reports.

[81]  S. Yokoyama,et al.  Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells , 1999, Oncogene.

[82]  Michael D. George,et al.  Apg5p functions in the sequestration step in the cytoplasm-to-vacuole targeting and macroautophagy pathways. , 2000, Molecular biology of the cell.

[83]  P. Seglen,et al.  Disruption of the cytokeratin cytoskeleton and inhibition of hepatocytic autophagy by okadaic acid. , 1995, Experimental cell research.

[84]  W. Bursch,et al.  Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. , 1996, Carcinogenesis.

[85]  W. Dunn,et al.  Studies on the mechanisms of autophagy: formation of the autophagic vacuole , 1990, The Journal of cell biology.

[86]  J. Xiang,et al.  BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[87]  J. Mege,et al.  Virulent Brucella abortus Prevents Lysosome Fusion and Is Distributed within Autophagosome-Like Compartments , 1998, Infection and Immunity.

[88]  Tsviya Olender,et al.  The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy , 2001, Nature Genetics.

[89]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[90]  Yoshiaki Kamada,et al.  Apg13p and Vac8p Are Part of a Complex of Phosphoproteins That Are Required for Cytoplasm to Vacuole Targeting* , 2000, The Journal of Biological Chemistry.

[91]  A. Cuervo,et al.  Age-related Decline in Chaperone-mediated Autophagy* , 2000, The Journal of Biological Chemistry.

[92]  I. Nonaka,et al.  A novel form of autophagic vacuolar myopathy with late-onset and multiorgan involvement , 2003, Neurology.

[93]  L. Greene,et al.  Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[94]  K. Howell,et al.  In exocrine pancreas, the basolateral endocytic pathway converges with the autophagic pathway immediately after the early endosome , 1990, The Journal of cell biology.

[95]  Kazuya Nagano,et al.  Tor-Mediated Induction of Autophagy via an Apg1 Protein Kinase Complex , 2000, The Journal of cell biology.

[96]  D. Scheuner,et al.  Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[97]  E. Baehrecke Autophagic programmed cell death in Drosophila , 2003, Cell Death and Differentiation.

[98]  A. D. Grey A proposed refinement of the mitochondrial free radical theory of aging , 1997 .

[99]  H. Hibshoosh,et al.  Induction of autophagy and inhibition of tumorigenesis by beclin 1 , 1999, Nature.

[100]  D. L. Tuttle,et al.  Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles , 1992, Journal of cellular physiology.

[101]  K. von Figura,et al.  Role of LAMP-2 in lysosome biogenesis and autophagy. , 2002, Molecular biology of the cell.

[102]  M. Saarma,et al.  GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway , 2003, The Journal of cell biology.

[103]  C. Bauvy,et al.  Differentiation-dependent autophagy controls the fate of newly synthesized N-linked glycoproteins in the colon adenocarcinoma HT-29 cell line. , 1995, The Biochemical journal.

[104]  P. Seglen,et al.  Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. , 1985, Experimental cell research.

[105]  A. Matsuura,et al.  Structural and functional analyses of APG5, a gene involved in autophagy in yeast. , 1996, Gene.

[106]  A. Matsuura,et al.  Apg10p, a novel protein‐conjugating enzyme essential for autophagy in yeast , 1999, The EMBO journal.

[107]  Michael D. George,et al.  A protein conjugation system essential for autophagy , 1998, Nature.

[108]  A. Tolkovsky,et al.  Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis , 2001, Current Biology.

[109]  W. Bursch,et al.  Autophagic and apoptotic types of programmed cell death exhibit different fates of cytoskeletal filaments. , 2000, Journal of cell science.

[110]  H. Tokumitsu,et al.  Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. , 1998, Biochemical and biophysical research communications.

[111]  Tibor Vellai,et al.  Genetics: Influence of TOR kinase on lifespan in C. elegans , 2003, Nature.

[112]  D. Figarella-Branger,et al.  X-linked myopathy with excessive autophagy: a clinicopathological study of five new families , 2001, Neuromuscular Disorders.

[113]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[114]  J. Hammarback,et al.  Molecular characterization of light chain 3. A microtubule binding subunit of MAP1A and MAP1B. , 1994, The Journal of biological chemistry.

[115]  Nektarios Tavernarakis,et al.  Death by necrosis , 2002 .

[116]  D. Klionsky,et al.  Apg7p/Cvt2p is required for the cytoplasm-to-vacuole targeting, macroautophagy, and peroxisome degradation pathways. , 1999, Molecular biology of the cell.

[117]  N. Mizushima,et al.  Apg7p/Cvt2p: A novel protein-activating enzyme essential for autophagy. , 1999, Molecular biology of the cell.

[118]  D. Klionsky,et al.  Apg9p/Cvt7p Is an Integral Membrane Protein Required for Transport Vesicle Formation in the Cvt and Autophagy Pathways , 2000, The Journal of cell biology.

[119]  Alexei Degterev,et al.  Diversity in the Mechanisms of Neuronal Cell Death , 2003, Neuron.

[120]  D. Brenner,et al.  The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. , 1998, Biochimica et biophysica acta.

[121]  P. Seglen,et al.  Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity. , 1992, The Biochemical journal.

[122]  G. Réz,et al.  Cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells. , 1999, Carcinogenesis.

[123]  J. Seidman,et al.  Hereditary inclusion body myopathy maps to chromosome 9p1-q1. , 1996, Human molecular genetics.

[124]  Z. Elazar,et al.  The COOH Terminus of GATE-16, an Intra-Golgi Transport Modulator, Is Cleaved by the Human Cysteine Protease HsApg4A* , 2003, The Journal of Biological Chemistry.

[125]  S. Mitrani‐Rosenbaum,et al.  Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy , 2003, Neurology.

[126]  Xose S. Puente,et al.  Human Autophagins, a Family of Cysteine Proteinases Potentially Implicated in Cell Degradation by Autophagy* , 2003, The Journal of Biological Chemistry.

[127]  P. Seglen,et al.  Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. , 1993, Carcinogenesis.

[128]  Y. Masuho,et al.  Interaction of the Unc-51-like kinase and microtubule-associated protein light chain 3 related proteins in the brain: possible role of vesicular transport in axonal elongation. , 2000, Brain research. Molecular brain research.

[129]  M. Komatsu,et al.  The C-terminal Region of an Apg7p/Cvt2p Is Required for Homodimerization and Is Essential for Its E1 Activity and E1-E2 Complex Formation* , 2001, The Journal of Biological Chemistry.

[130]  D. Hall,et al.  Autophagy Genes Are Essential for Dauer Development and Life-Span Extension in C. elegans , 2003, Science.

[131]  S. Emr,et al.  A Multispecificity Syntaxin Homologue, Vam3p, Essential for Autophagic and Biosynthetic Protein Transport to the Vacuole , 1997, The Journal of cell biology.

[132]  U. Brunk,et al.  The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. , 2002, European journal of biochemistry.

[133]  R. Parsons,et al.  The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. , 1998, Cancer research.

[134]  Y. Ohsumi,et al.  Ubiquitin and proteasomes: Molecular dissection of autophagy: two ubiquitin-like systems , 2001, Nature Reviews Molecular Cell Biology.

[135]  N. Mizushima,et al.  Coronavirus Replication Complex Formation Utilizes Components of Cellular Autophagy* , 2004, Journal of Biological Chemistry.

[136]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[137]  D. Sulzer,et al.  Autophagy in neurons: a review. , 2002, Histology and histopathology.

[138]  R. Kopito,et al.  Aggresomes, inclusion bodies and protein aggregation. , 2000, Trends in cell biology.

[139]  S. Emr,et al.  Vam7p, a SNAP-25-Like Molecule, and Vam3p, a Syntaxin Homolog, Function Together in Yeast Vacuolar Protein Trafficking , 1998, Molecular and Cellular Biology.

[140]  P. Seglen,et al.  Amino acid control of protein degradation in normal and leukemic human lymphocytes. , 1984, Experimental cell research.

[141]  J. Teckman,et al.  Mitochondrial autophagy and injury in the liver in α1-antitrypsin deficiency , 2004 .

[142]  P. De Camilli,et al.  Phosphoinositides as Regulators in Membrane Traffic , 1996, Science.

[143]  S. Emr,et al.  Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy , 2002, The Journal of cell biology.

[144]  N. Mizushima,et al.  A New Protein Conjugation System in Human , 1998, The Journal of Biological Chemistry.