lysosomes

Summary

Summary: A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured. Such rupture is supposed to be under metabolic (hormonal) control. (From Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)

Top Publications

  1. pmc Autophagy in the pathogenesis of disease
    Beth Levine
    Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Cell 132:27-42. 2008
  2. pmc Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations
    Ju Hyun Lee
    Center for Dementia Research, Nathan S Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA
    Cell 141:1146-58. 2010
  3. pmc p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death
    Geir Bjørkøy
    Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway
    J Cell Biol 171:603-14. 2005
  4. ncbi Development by self-digestion: molecular mechanisms and biological functions of autophagy
    Beth Levine
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Dev Cell 6:463-77. 2004
  5. pmc Inhibition of macroautophagy triggers apoptosis
    Patricia Boya
    CNRS UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, F 94805 Villejuif, France
    Mol Cell Biol 25:1025-40. 2005
  6. ncbi Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages
    Maximiliano G Gutierrez
    Instituto de Histologia y Embriologia, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo CONICET, Mendoza 5500, Argentina
    Cell 119:753-66. 2004
  7. ncbi Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3
    Shunsuke Kimura
    Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
    Autophagy 3:452-60. 2007
  8. pmc Regulation mechanisms and signaling pathways of autophagy
    Congcong He
    Life Sciences Institute and Departments of Molecular, Cellular and Developmental Biology, and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
    Annu Rev Genet 43:67-93. 2009
  9. pmc Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids
    Yasemin Sancak
    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
    Cell 141:290-303. 2010
  10. ncbi Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy
    Isei Tanida
    Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
    Autophagy 1:84-91. 2005

Detail Information

Publications403 found, 100 shown here

  1. pmc Autophagy in the pathogenesis of disease
    Beth Levine
    Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Cell 132:27-42. 2008
    ..This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases...
  2. pmc Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations
    Ju Hyun Lee
    Center for Dementia Research, Nathan S Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA
    Cell 141:1146-58. 2010
    ..These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the ..
  3. pmc p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death
    Geir Bjørkøy
    Biochemistry Department, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway
    J Cell Biol 171:603-14. 2005
    ..We suggest that p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery...
  4. ncbi Development by self-digestion: molecular mechanisms and biological functions of autophagy
    Beth Levine
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Dev Cell 6:463-77. 2004
    ..In this review, we summarize our current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development...
  5. pmc Inhibition of macroautophagy triggers apoptosis
    Patricia Boya
    CNRS UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, F 94805 Villejuif, France
    Mol Cell Biol 25:1025-40. 2005
    ..Under conditions in which the fusion between lysosomes and autophagosomes was inhibited, the formation of autophagic vacuoles was enhanced at a preapoptotic stage, as ..
  6. ncbi Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages
    Maximiliano G Gutierrez
    Instituto de Histologia y Embriologia, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo CONICET, Mendoza 5500, Argentina
    Cell 119:753-66. 2004
    ..tuberculosis. Autophagy, which is a hormonally, developmentally, and, as shown here, immunologically regulated process, represents an underappreciated innate defense mechanism for control of intracellular pathogens...
  7. ncbi Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3
    Shunsuke Kimura
    Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
    Autophagy 3:452-60. 2007
    ..of autophagy, autophagosomes undergo a maturation process consisting of multiple fusions with endosomes and lysosomes, which provide an acidic environment and digestive function to the interior of the autophagosome...
  8. pmc Regulation mechanisms and signaling pathways of autophagy
    Congcong He
    Life Sciences Institute and Departments of Molecular, Cellular and Developmental Biology, and Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
    Annu Rev Genet 43:67-93. 2009
    ..components in which double-membrane autophagosomes sequester organelles or portions of cytosol and fuse with lysosomes or vacuoles for breakdown by resident hydrolases...
  9. pmc Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids
    Yasemin Sancak
    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
    Cell 141:290-303. 2010
    ..MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation...
  10. ncbi Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy
    Isei Tanida
    Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
    Autophagy 1:84-91. 2005
    During starvation-induced autophagy in mammals, autophagosomes form and fuse with lysosomes, leading to the degradation of the intra-autophagosomal contents by lysosomal proteases...
  11. ncbi Growth factor regulation of autophagy and cell survival in the absence of apoptosis
    Julian J Lum
    Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Cell 120:237-48. 2005
    ..Thus, growth factor signal transduction is required to direct the utilization of sufficient exogenous nutrients to maintain cell viability...
  12. pmc Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease
    Barry Boland
    Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York 10962, USA
    J Neurosci 28:6926-37. 2008
    ..cortical neurons is highly efficient, because newly formed autophagosomes are rapidly cleared by fusion with lysosomes, accounting for their scarcity in the healthy brain...
  13. ncbi LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation
    Yukiko Kabeya
    Department of Cell Biology, National Institute for Basic Biology, Myodaiji 38, Okazaki 444 8585, Japan
    J Cell Sci 117:2805-12. 2004
    ..Generation of the form II correlates with autophagosome association of GABARAP and GATE16. These results suggest that all mammalian Atg8 homologues receive a common modification to associate with autophagosomal membrane as the form II...
  14. pmc Termination of autophagy and reformation of lysosomes regulated by mTOR
    Li Yu
    Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
    Nature 465:942-6. 2010
    ..In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients...
  15. pmc In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker
    Noboru Mizushima
    Department of Cell Biology, National Institute for Basic Biology, Okazaki 444 8585, Japan
    Mol Biol Cell 15:1101-11. 2004
    ..constituents, including organelles, are sequestered into autophagosomes, which subsequently fuse with lysosomes, where degradation occurs...
  16. pmc mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase
    Roberto Zoncu
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
    Science 334:678-83. 2011
    ..These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing...
  17. pmc Autophagy: molecular machinery for self-eating
    T Yorimitsu
    Department of Molecular, Cellular and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA
    Cell Death Differ 12:1542-52. 2005
    ..Analyses in a range of model systems have provided huge advances toward understanding the molecular basis of autophagy. Here we review our current knowledge on the machinery and molecular mechanism of autophagy...
  18. ncbi Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy
    Ana Maria Cuervo
    Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Science 305:1292-5. 2004
    ..We found that wild-type alpha-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway...
  19. pmc TFEB links autophagy to lysosomal biogenesis
    Carmine Settembre
    Telethon Institute of Genetics and Medicine TIGEM, Via Pietro Castellino 111, 80131 Naples, Italy
    Science 332:1429-33. 2011
    Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes...
  20. pmc Autophagy: assays and artifacts
    Sandra Barth
    Ben May Department for Cancer Research, Gordon Center for Integrative Sciences, University of Chicago, IL, USA
    J Pathol 221:117-24. 2010
    ..by the formation of double-layered vesicles (autophagosomes) around intracellular cargo for delivery to lysosomes and proteolytic degradation...
  21. ncbi How to interpret LC3 immunoblotting
    Noboru Mizushima
    Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan
    Autophagy 3:542-5. 2007
    ..does not indicate autophagic flux, and therefore, it is important to measure the amount of LC3-II delivered to lysosomes by comparing LC3-II levels in the presence and absence of lysosomal protease inhibitors...
  22. ncbi Autophagy defends cells against invading group A Streptococcus
    Ichiro Nakagawa
    Department of Oral and Molecular Microbiology, Osaka University Graduate School of Dentistry, 1 8 Yamadaoka, Suita Osaka 565 0871, Japan
    Science 306:1037-40. 2004
    ..GAS became enveloped by autophagosome-like compartments and were killed upon fusion of these compartments with lysosomes. In autophagy-deficient Atg5-/- cells, GAS survived, multiplied, and were released from the cells...
  23. ncbi Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells
    A Yamamoto
    Department of Physiology and Liver Research Center Cell Biology, Kansai Medical University, Osaka, Japan
    Cell Struct Funct 23:33-42. 1998
    ..which accumulated in the presence of bafilomycin A1, suggesting that fusion between autophagosomes and lysosomes was disturbed by this drug...
  24. pmc HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy
    Joo Yong Lee
    Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
    EMBO J 29:969-80. 2010
    ..HDAC6 is not required for autophagy activation; rather, it controls the fusion of autophagosomes to lysosomes. HDAC6 promotes autophagy by recruiting a cortactin-dependent, actin-remodelling machinery, which in turn ..
  25. pmc Rab7: a key to lysosome biogenesis
    C Bucci
    Structural Cell Biology Unit, Department of Medical Anatomy, The Panum Institute, University of Copenhagen, DK 2200 Copenhagen, Denmark
    Mol Biol Cell 11:467-80. 2000
    ..being part of this machinery is the small GTPase Rab7, but it is unclear whether this protein is associated with lysosomes or plays any role in the regulation of the perinuclear lysosome compartment...
  26. pmc Autophagy regulates lipid metabolism
    Rajat Singh
    Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA
    Nature 458:1131-5. 2009
    ..which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source...
  27. pmc Microautophagy of cytosolic proteins by late endosomes
    Ranjit Sahu
    Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    Dev Cell 20:131-9. 2011
    Autophagy delivers cytosolic components to lysosomes for their degradation. The delivery of autophagic cargo to late endosomes for complete or partial degradation has also been described...
  28. pmc Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies
    Joseph R Mazzulli
    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA
    Cell 146:37-52. 2011
    ..Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
  29. pmc Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization
    Anwari Akhter
    Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA
    Immunity 37:35-47. 2012
    ..pneumophila infection in human macrophages. Caspase-11 promoted the fusion of the L. pneumophila vacuole with lysosomes by modulating actin polymerization through cofilin...
  30. pmc Transcriptional activation of lysosomal exocytosis promotes cellular clearance
    Diego L Medina
    Telethon Institute of Genetics and Medicine TIGEM, Via P Castellino 111, 80131 Naples, Italy
    Dev Cell 21:421-30. 2011
    b>Lysosomes are cellular organelles primarily involved in degradation and recycling processes...
  31. pmc HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes
    Yukie Iwabu
    Department of Pathology, National Institute of Infectious Diseases, Tokyo 162 8640, Japan
    J Biol Chem 284:35060-72. 2009
    ..Also, we propose the following configuration of BST-2 in tethering virions to the cell surface; each of the dimerized BST-2 molecules acts as a bridge between viral and cell membranes...
  32. pmc Ubiquitin signals autophagic degradation of cytosolic proteins and peroxisomes
    Peter Kijun Kim
    Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
    Proc Natl Acad Sci U S A 105:20567-74. 2008
    ..e., peroxisomes) substrates are efficiently targeted to autophagosomes and then degraded within lysosomes upon autophagosome-lysosome fusion...
  33. ncbi The familial Parkinsonism gene LRRK2 regulates neurite process morphology
    David Macleod
    Departments of Pathology and Neurology, Center for Neurobiology and Behavior and Taub Institute, Columbia University, College of Physicians and Surgeons 15 403, 630 West 168th Street, New York, New York 10032, USA
    Neuron 52:587-93. 2006
    ..Neurons that express PD-associated LRRK2 mutations additionally harbor prominent phospho-tau-positive inclusions with lysosomal characteristics and ultimately undergo apoptosis...
  34. doi The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes
    Eisuke Itakura
    Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113 8519, Japan
    Cell 151:1256-69. 2012
    ..These findings reveal a mechanism by which the SNARE protein is available to the completed autophagosome...
  35. ncbi HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin
    Atsushi Iwata
    Department of Biological Sciences, Bio X Program, Stanford University, Stanford, California 94305 5430, USA
    J Biol Chem 280:40282-92. 2005
    ..We show that ATG proteins, molecular determinants of autophagic vacuole formation, and lysosomes are recruited to pericentriolar cytoplasmic inclusion bodies by a process requiring an intact microtubule ..
  36. ncbi Lysosomes: fusion and function
    J Paul Luzio
    Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK
    Nat Rev Mol Cell Biol 8:622-32. 2007
    b>Lysosomes are dynamic organelles that receive and degrade macromolecules from the secretory, endocytic, autophagic and phagocytic membrane-trafficking pathways...
  37. pmc Lysosomal positioning coordinates cellular nutrient responses
    Viktor I Korolchuk
    Department of Medical Genetics, Cambridge Institute for Medical Genetics, Wellcome Trust MRC Building, Hills Road, Cambridge, CB2 0XY, UK
    Nat Cell Biol 13:453-60. 2011
    ..However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles intimately involved both in the activation of mTOR complex 1 (mTORC1) ..
  38. ncbi TLR9 signals after translocating from the ER to CpG DNA in the lysosome
    Eicke Latz
    Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Lazare Research Building 308, 364 Plantation Street, Worcester, MA 01605, USA
    Nat Immunol 5:190-8. 2004
    ..Our data indicate a previously unknown mechanism of cellular activation involving the recruitment of TLR9 from the ER to sites of CpG DNA uptake, where signal transduction is initiated...
  39. pmc Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes
    Monique Gannage
    Viral Immunobiology, Institute of Experimental Immunology, University Hospital of Zurich, 8057 Zurich, Switzerland
    Cell Host Microbe 6:367-80. 2009
    ..Influenza A virus infection causes accumulation of autophagosomes by blocking their fusion with lysosomes, and one viral protein, matrix protein 2, is necessary and sufficient for this inhibition of autophagosome ..
  40. pmc LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis
    Hilla Weidberg
    Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel
    EMBO J 29:1792-802. 2010
    ..Accordingly, our results indicate that LC3s are involved in elongation of the phagophore membrane whereas the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation...
  41. pmc Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis
    Joanna Rejman
    Department of Membrane Cell Biology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands
    Biochem J 377:159-69. 2004
    ..At these conditions, delivery to the lysosomes was no longer apparent...
  42. pmc A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB
    Carmine Settembre
    Telethon Institute of Genetics and Medicine, Naples, Italy
    EMBO J 31:1095-108. 2012
    ..These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR...
  43. ncbi Organelle-specific initiation of cell death pathways
    K F Ferri
    Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
    Nat Cell Biol 3:E255-63. 2001
    ..Accumulating evidence suggests that other organelles, including the endoplasmic reticulum (ER), lysosomes and the Golgi apparatus, are also major points of integration of pro-apoptotic signalling or damage sensing...
  44. pmc Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9
    Boyoun Park
    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02115, USA
    Nat Immunol 9:1407-14. 2008
    ..Lysosomal proteolysis thus contributes to innate immunity by facilitating specific cleavage of TLR9...
  45. ncbi Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation
    P Kavsak
    Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada
    Mol Cell 6:1365-75. 2000
    ..These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation...
  46. pmc Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease
    Marta Martinez-Vicente
    Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, USA
    Nat Neurosci 13:567-76. 2010
    ..Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen...
  47. ncbi Eating oneself and uninvited guests: autophagy-related pathways in cellular defense
    Beth Levine
    Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75330, USA
    Cell 120:159-62. 2005
    ..2005). Other recent studies indicate that the autophagy machinery is also used to degrade foreign microbial invaders (xenophagy)...
  48. ncbi Intracellular functions of N-linked glycans
    A Helenius
    Institute of Biochemistry, , , , Switzerland
    Science 291:2364-9. 2001
    ..The division of synthesis and processing between the ER and the Golgi complex represents an evolutionary adaptation that allows efficient exploitation of the potential of oligosaccharides...
  49. ncbi Lysosomes and autophagy in cell death control
    Guido Kroemer
    CNRS UMR8125, Institut Gustave Roussy, 38 rue Camille Desmoulins, F 94805 Villejuif, France
    Nat Rev Cancer 5:886-97. 2005
    ..Similarly, alterations in the autophagic compartment are linked to carcinogenesis and resistance to chemotherapy. Targeting these pathways might constitute a novel approach to cancer therapy...
  50. pmc The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor
    Sarah E Ewald
    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, 405 Life Sciences Addition, Berkeley, California 94720 3200, USA
    Nature 456:658-62. 2008
    ..We propose that ectodomain cleavage represents a strategy to restrict receptor activation to endolysosomal compartments and prevent TLRs from responding to self nucleic acids...
  51. ncbi Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes
    Shigeomi Shimizu
    Department of Post Genomics and Diseases, Osaka University Medical School, 2 2 Yamadaoka, Suita, Osaka 565 0871, Japan
    Nat Cell Biol 6:1221-8. 2004
    ..These results indicate that the Bcl-2 family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes...
  52. pmc Amino acids and mTORC1: from lysosomes to disease
    Alejo Efeyan
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
    Trends Mol Med 18:524-33. 2012
    ..The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies...
  53. pmc Autophagic cell death: the story of a misnomer
    Guido Kroemer
    Institut Gustave Roussy, F 94805 Villejuif, France
    Nat Rev Mol Cell Biol 9:1004-10. 2008
    ..We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death...
  54. ncbi Autophagy, amyloidogenesis and Alzheimer disease
    Ralph A Nixon
    Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
    J Cell Sci 120:4081-91. 2007
    ..Abeta generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively form in synapses and along neuritic processes but ..
  55. doi C. elegans screen identifies autophagy genes specific to multicellular organisms
    Ye Tian
    National Institute of Biological Sciences, Beijing 102206, P R China
    Cell 141:1042-55. 2010
    ..This study establishes C. elegans as a multicellular genetic model to delineate the autophagy pathway and provides mechanistic insights into the metazoan-specific autophagic process...
  56. pmc Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP
    Patricia Gómez-Suaga
    Institute of Parasitology and Biomedicine Lo pez Neyra, Consejo Superior de Investigaciones Cientificas, Avda del Conocimiento s n, 18100 Granada, Spain
    Hum Mol Genet 21:511-25. 2012
    ..levels of the autophagy receptor p62 in a protein synthesis-dependent manner, and decreases the number of acidic lysosomes. The LRRK2-mediated effects result in increased sensitivity of cells to stressors associated with abnormal ..
  57. pmc Microglial migration mediated by ATP-induced ATP release from lysosomes
    Ying Dou
    Institute of Neuroscience and Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
    Cell Res 22:1022-33. 2012
    ..However, the mechanisms of the long-range migration of microglia remain to be clarified. Here, we found that lysosomes in microglia contain abundant ATP and exhibit Ca(2+)-dependent exocytosis in response to various stimuli...
  58. pmc Clarifying lysosomal storage diseases
    Mark L Schultz
    Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
    Trends Neurosci 34:401-10. 2011
    ..In this review, we provide an overview of the widespread cellular perturbations occurring in LSDs, how they might be linked and interventions that may specifically or globally correct those defects...
  59. doi Cationic polystyrene nanosphere toxicity depends on cell-specific endocytic and mitochondrial injury pathways
    Tian Xia
    Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, California 90095, USA
    ACS Nano 2:85-96. 2008
    ..Taken together, the results of this study demonstrate the importance of cell-specific uptake mechanisms and pathways that could lead to sensitivity or resistance to cationic particle toxicity...
  60. doi Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways
    Michela Palmieri
    Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute at Texas Children s Hospital, Houston, TX, USA
    Hum Mol Genet 20:3852-66. 2011
    In metazoans, lysosomes are the center for the degradation of macromolecules and play a key role in a variety of cellular processes, such as autophagy, exocytosis and membrane repair...
  61. pmc Autophagy as a regulated pathway of cellular degradation
    D J Klionsky
    Department of Biology, University of Michigan, 830 North University, Ann Arbor, MI 48109 1048, USA
    Science 290:1717-21. 2000
    ..Macroautophagy plays an important role in developmental processes, human disease, and cellular response to nutrient deprivation...
  62. pmc Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol
    Hyock Joo Kwon
    Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 9046, USA
    Cell 137:1213-24. 2009
    LDL delivers cholesterol to lysosomes by receptor-mediated endocytosis. Exit of cholesterol from lysosomes requires two proteins, membrane-bound Niemann-Pick C1 (NPC1) and soluble NPC2...
  63. ncbi A block of autophagy in lysosomal storage disorders
    Carmine Settembre
    Telethon Institute of Genetics and Medicine TIGEM, Naples, Italy
    Hum Mol Genet 17:119-29. 2008
    ..Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase ..
  64. pmc Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy
    Marta Martinez-Vicente
    Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA
    J Clin Invest 118:777-88. 2008
    ..Using mouse ventral medial neuron cultures, SH-SY5Y cells in culture, and isolated mouse lysosomes, we have found that most of these posttranslational modifications of alpha-syn impair degradation of this ..
  65. ncbi Lysosome-related organelles
    E C Dell'Angelica
    Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892 5430, USA
    FASEB J 14:1265-78. 2000
    b>Lysosomes are membrane-bound cytoplasmic organelles involved in intracellular protein degradation. They contain an assortment of soluble acid-dependent hydrolases and a set of highly glycosylated integral membrane proteins...
  66. pmc Regulation of TFEB and V-ATPases by mTORC1
    Samuel Peña-Llopis
    Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    EMBO J 30:3242-58. 2011
    ..These data uncover a regulatory network linking an oncogenic transcription factor that is a master regulator of lysosomal biogenesis, TFEB, to mTORC1 and endocytosis...
  67. doi Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium
    Emyr Lloyd-Evans
    Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK
    Nat Med 14:1247-55. 2008
    ..This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse...
  68. pmc Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling
    Eugen Brailoiu
    Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA
    J Cell Biol 186:201-9. 2009
    ..Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP...
  69. pmc Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits
    Dun Sheng Yang
    Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA
    Brain 134:258-77. 2011
    ..accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide...
  70. pmc Dissecting the dynamic turnover of GFP-LC3 in the autolysosome
    Hong Min Ni
    Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
    Autophagy 7:188-204. 2011
    ....
  71. ncbi Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation
    Da Wei Zhang
    Department of Molecular Genetics, The Donald W Reynolds Cardiovascular Clinical Research Center, Howard Hughes Institute, University of Texas Southwestern Medical Center, Dallas 75390, USA
    J Biol Chem 282:18602-12. 2007
    ..to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes. These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent ..
  72. pmc Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing
    Yipeng Wang
    Max Planck Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany
    Hum Mol Genet 18:4153-70. 2009
    ..of a selective form of autophagy, chaperone-mediated autophagy, are involved in the delivery of cytosolic Tau to lysosomes for this limited cleavage...
  73. doi The proteome of lysosomes
    Bernd A Schröder
    Biochemical Institute, Christian Albrechts University, Kiel, Germany
    Proteomics 10:4053-76. 2010
    b>Lysosomes are organelles of eukaryotic cells that are critically involved in the degradation of macromolecules mainly delivered by endocytosis and autophagocytosis...
  74. ncbi Maturation of autophagic vacuoles in Mammalian cells
    Eeva Liisa Eskelinen
    Institute of Biochemistry, University of Kiel, Germany
    Autophagy 1:1-10. 2005
    ..This suggests that autophagy has important housekeeping or protective functions because a block in autophagic maturation causes a disease...
  75. doi Autophagy and multivesicular bodies: two closely related partners
    C M Fader
    Laboratorio de Biologia Celular y Molecular, Instituto de Histologia y Embriologia IHEM CONICET, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo, Casilla de Correo 56, Centro Universitario, Parque General San Martín, 5500 Mendoza, Argentina
    Cell Death Differ 16:70-8. 2009
    ..This review highlights the most recent advances in our understanding of the molecular machinery that participates in MVB biogenesis and regulates the interplay between autophagy and this organelle...
  76. doi Lysosomes and lysosomal cathepsins in cell death
    Urska Repnik
    Department of Biochemistry and Molecular and Structural Biology, J Stefan Institute, Jamova, Ljubljana, Slovenia
    Biochim Biophys Acta 1824:22-33. 2012
    b>Lysosomes are the key degradative compartments of the cell...
  77. doi The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease
    Tianhong Pan
    Parkinson s Disease Research Laboratory, Baylor College of Medicine, Houston, TX 77030, USA
    Brain 131:1969-78. 2008
    ..In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement...
  78. ncbi Autophagy: process and function
    Noboru Mizushima
    Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113 8519, Japan
    Genes Dev 21:2861-73. 2007
    ..Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function...
  79. doi Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
    Viola Hélène Lobert
    Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway
    Dev Cell 19:148-59. 2010
    ..alpha 5 beta 1 integrin, is sorted into multivesicular endosomes together with fibronectin and degraded in lysosomes. This sorting requires fibronectin-induced ubiquitination of the alpha 5 subunit, and the activity of the ..
  80. pmc The molecular machinery of autophagy: unanswered questions
    Daniel J Klionsky
    Life Sciences Institute, Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
    J Cell Sci 118:7-18. 2005
    ....
  81. pmc Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes
    Anne Simonsen
    Department of Biochemistry, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway
    J Cell Biol 186:773-82. 2009
    ..Here we discuss the cross talk between autophagy and intracellular compartments, highlighting recent exciting data about the role and regulation of the Vps34 class III phosphatidylinositol (PI) 3-kinase in autophagy...
  82. ncbi Does bafilomycin A1 block the fusion of autophagosomes with lysosomes?
    Daniel J Klionsky
    Autophagy 4:849-950. 2008
    ..H(+)-ATPase (V-ATPase) in cells, and inhibits the acidification of organelles containing this enzyme, such as lysosomes and endosomes...
  83. pmc LAMP proteins are required for fusion of lysosomes with phagosomes
    Kassidy K Huynh
    Division of Cell Biology, The Hospital for Sick Children, Toronto, Canada
    EMBO J 26:313-24. 2007
    ..Macrophages from LAMP-1- or LAMP-2-deficient mice displayed normal fusion of lysosomes with phagosomes...
  84. pmc Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson's disease
    Ruben K Dagda
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    Autophagy 4:770-82. 2008
    ..These data indicate that mitochondrial localization of ERK2 activity is sufficient to recapitulate the effects of 6-OHDA on mitophagy and autophagic cell death...
  85. pmc Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents
    Michael Degtyarev
    Genentech, Inc, South San Francisco, CA 94080, USA
    J Cell Biol 183:101-16. 2008
    ....
  86. ncbi Autophagosome formation: core machinery and adaptations
    Zhiping Xie
    Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology and Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
    Nat Cell Biol 9:1102-9. 2007
    ..is the formation of autophagosomes, double-membrane vesicles responsible for delivering cytoplasmic material to lysosomes. In the past decade many autophagy-related genes, ATG, have been identified that are required for selective and/..
  87. pmc Accumulation of rhodopsin in late endosomes triggers photoreceptor cell degeneration
    Yashodhan Chinchore
    Department of Biology, Dartmouth College, Hanover, New Hampshire, United States of America
    PLoS Genet 5:e1000377. 2009
    ..Together these data implicate buildup of rhodopsin in the late endosomal system as a novel trigger of death of photoreceptor neurons...
  88. doi Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function
    Paul Saftig
    Department of Biochemistry, Christian Albrechts University, Kiel, Germany
    Nat Rev Mol Cell Biol 10:623-35. 2009
    b>Lysosomes are the primary catabolic compartments of eukaryotic cells. They degrade extracellular material that has been internalized by endocytosis and intracellular components that have been sequestered by autophagy...
  89. ncbi Signals for sorting of transmembrane proteins to endosomes and lysosomes
    Juan S Bonifacino
    Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
    Annu Rev Biochem 72:395-447. 2003
    Sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present within the cytosolic domains of the proteins. Most signals consist of short, linear sequences of amino acid residues...
  90. pmc Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes
    Wan Seob Cho
    ELEGI Group, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
    Part Fibre Toxicol 8:27. 2011
    ..Herein, we further investigated the pathological changes induced by ZnONP and their possible mechanism of action...
  91. pmc Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer
    Matthew N J Seaman
    Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, England, UK
    J Cell Biol 165:111-22. 2004
    ..The data presented here support the hypothesis that retromer performs a selective function in endosome-to-Golgi transport, mediating retrieval of the CI-MPR, but not furin...
  92. ncbi Drosophila Vps16A is required for trafficking to lysosomes and biogenesis of pigment granules
    Suprabha Pulipparacharuvil
    Center for Basic Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9111, USA
    J Cell Sci 118:3663-73. 2005
    Mutations that disrupt trafficking to lysosomes and lysosome-related organelles cause multiple diseases, including Hermansky-Pudlak syndrome. The Drosophila eye is a model system for analyzing such mutations...
  93. ncbi The roles of intracellular protein-degradation pathways in neurodegeneration
    David C Rubinsztein
    Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2XY
    Nature 443:780-6. 2006
    ..However, enhancing macroautophagy with drugs such as rapamycin could offer a tractable therapeutic strategy for a number of these diseases...
  94. ncbi The mitochondrial permeability transition initiates autophagy in rat hepatocytes
    S P Elmore
    Department of Cell and Developmental Biology and Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599, USA
    FASEB J 15:2286-7. 2001
    ..In conclusion, the MPT initiates mitochondrial depolarization after autophagic stimulation and the subsequent sequestration of mitochondria into autophagosomes...
  95. doi The late stages of autophagy: how does the end begin?
    T Noda
    Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, 3 1 Yamadaoka, Suita, Osaka 565 0871, Japan
    Cell Death Differ 16:984-90. 2009
    ..Finally, the molecular mechanisms involved in the delivery of autophagosomes to the lysosome and fusion are introduced. Several key events exist in each step and seem to be coordinated to faithfully conduct the autophagic process...
  96. ncbi Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation
    Kaisa Haglund
    Ludwig Institute for Cancer Research, Husargatan 3, SE 75 124 Uppsala, Sweden
    Nat Cell Biol 5:461-6. 2003
    ..Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome...
  97. ncbi Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis
    E D Carstea
    National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
    Science 277:228-31. 1997
    ....
  98. doi Peripheral protein quality control removes unfolded CFTR from the plasma membrane
    Tsukasa Okiyoneda
    Department of Physiology, and Groupe de Recherche Axé sur la Structure des Protéine GRASP McGill University, Montreal, Quebec H3G 1Y6, Canada
    Science 329:805-10. 2010
    ....
  99. doi The biomolecular corona is retained during nanoparticle uptake and protects the cells from the damage induced by cationic nanoparticles until degraded in the lysosomes
    Fengjuan Wang
    Centre for BioNano Interactions, School of Chemistry and Chemical Biology and UCD Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland Department of Cellular and Molecular Biology, CIB, CSIC, Ramiro de Maeztu 9, E 28040 Madrid, Spain
    Nanomedicine 9:1159-68. 2013
    ..adsorbed layer is strong enough to be retained on the nanoparticles as they enter cells and is trafficked to the lysosomes on the nanoparticles...
  100. pmc Autophagosome supports coxsackievirus B3 replication in host cells
    Jerry Wong
    The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia St Paul s Hospital, 1081 Burrard St, Vancouver, British Columbia, Canada
    J Virol 82:9143-53. 2008
    ..Taken together, our results suggest that the host's autophagy machinery is activated during CVB3 infection to enhance the efficiency of viral replication...
  101. pmc Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor
    L Foghsgaard
    Apoptosis Laboratory, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
    J Cell Biol 153:999-1010. 2001
    ..These data imply that cathepsin B, which is commonly overexpressed in human primary tumors, may have two opposing roles in malignancy, reducing it by its proapoptotic features and enhancing it by its known facilitation of invasion...

Research Grants72

  1. NIH Director's Pioneer Award
    Junying Yuan; Fiscal Year: 2009
    ..No Abstract provided ..
  2. Inhibition of human neutrophil function by Francisella tularensis
    Lee Ann H Allen; Fiscal Year: 2012
    ..The results of this study may lead to new treatments to combat this severe and often fatal lung infection. ..
  3. Mechanism-Based Discovery of Protectants Against Iron-Dependant Oxidative Injury
    JUSTIN M SCHWARTZ; Fiscal Year: 2011
    ..The majority of chelatable iron capable of catalyzing the Fenton chemistry is normally contained in lysosomes. Based on preliminary studies, it is probable that iron-dependent radical chemistry during oxidative stress ..
  4. Regulation of LPS-mediated HMGB1 Release by Poly (ADP-ribose) Polymerase-1
    RAJESH K ANEJA; Fiscal Year: 2013
    ..Under this aim, we will determine: 1) if LPS-mediated HMGB1 trafficking to the lysosomes requires PARP-1 activity;2) HMGB1 concentration in the lysosomes with or without PARP-1 inhibition 3) HMGB1 ..
  5. Local Calcium Signaling in Pulmonary Arteries
    JAMES SK SHAM; Fiscal Year: 2012
    ..The information generated by the proposed experiments will be valuable for the development of new treatments for pulmonary vascular diseases. ..
  6. The Mucolipin TRP Ion Channels
    Haoxing Xu; Fiscal Year: 2013
    ..Transient Receptor Potential (TRPML) proteins is predicted to encode ion channels of intracellular endosomes and lysosomes. Mutations of human TRPML1 cause type IV mucolipidosis (ML4), a devastating neurodegenerative disease in young ..
  7. Adipose Tissue Macrophage Phenotype and Function
    Anthony W Ferrante; Fiscal Year: 2013
    ..role of lipolysis in the chronic recruitment and accumulation of ATMs in obesity 2) To determine the role of ATM lysosomes and autophagy in function ATMs and adipose tissue metabolism 3) To characterize the role of ATM-derived IGF-1 ..
  8. CELLULAR REGULATION OF CLATHRIN ASSEMBLY AND FUNCTION
    Frances M Brodsky; Fiscal Year: 2013
    ....
  9. Regulation of Fibronectin Matrix Assembly by uPAR
    PAULA J MC KEOWN-LONGO; Fiscal Year: 2012
    ..Experiments will evaluate whether uPAR-mediated EGFR transactivation reroutes the trafficking of EGFR from lysosomes and into focal adhesions where it forms complexes with the 1521 integrin...
  10. Neprilysin and Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms
    EDWARD CHARLES DEMPSEY; Fiscal Year: 2013
    ..and expression (focus on reactive oxygen and nitrogen species [ROS/RNS] leading to protein degradation by lysosomes and proteasomes and decreased gene expression mediated by the hypoxia-induced transcription factors HIF-1 and ..
  11. Molecular Regulation of Alpha-Synuclein Misfolding and Toxicity in Two Yeast Mode
    SHUBHIK DEBBURMAN; Fiscal Year: 2009
    ....
  12. STRUCTURE OF THE VACUOLAR ATPase
    Stephan Wilkens; Fiscal Year: 2013
    ..of a wide variety of intracellular compartments like clathrin-coated vesicles, chromaffin granules, endosomes, lysosomes, synaptic vesicles, Golgi derived vesicles and the yeast vacuole...
  13. Control of liver autophagy by phosphatidic acid signaling
    GILBERT DIPAOLO; Fiscal Year: 2013
    ..is to promote the maturation of autophagosomes by facilitating the fusion of these organelles with endosomes/lysosomes. Together with preliminary observations showing that lipid droplets are more prominent in Pld1 knockout liver ..
  14. Disease-related defects in dendritic cell processing of bacterial antigens
    Michael S Marks; Fiscal Year: 2012
    ..monocytogenes) in vivo. 2. To test whether LRO biogenesis and/or phagosome maturation in bone marrow-derived DCs (BMDCs) is altered in HPS mouse models lacking BLOC-1 or AP-3. ..
  15. Autophagy and human islet amyloid polypeptide in animal models of type 2 diabetes
    Jacqueline Rivera; Fiscal Year: 2013
    ..We will utilize fluorescently-labeled proteins that localize to autophagosomes or lysosomes to visualize transport and fusion abnormalities in real time experiments by confocal microscopy (live cell ..
  16. Mechanisms of Ubiquitin Trafficking in Neurons
    Michael C Wooten; Fiscal Year: 2013
    ....
  17. The role of acyl-CoA binding proteins in selective autophagy
    Taras Y Nazarko; Fiscal Year: 2013
    ..Recent studies in the autophagy field suggest that LDs can be selectively delivered to and degraded by lysosomes. This discovery has opened an exciting, new opportunity to correct lipid metabolism in humans by modulating ..
  18. Liver Cell Membrane Protein-Expression and Function
    Allan W Wolkoff; Fiscal Year: 2012
    ..trafficking steps in endocytosis mutants (Project 3), and mechanisms of trafficking to autophagic vacuoles and lysosomes (Project 4)...
  19. Mechanisms of ENaC Inhibition by Replicating Influenza Virus: Role of M2 Protein
    Sadis Matalon; Fiscal Year: 2012
    ....
  20. Rescuing Niemann-Pick C Disease: Pathways of Liver and Brain Degeneration
    Matthew P Scott; Fiscal Year: 2013
    ..Loss of either gene causes aberrant organelle trafficking and accumulation of free cholesterol within lysosomes. NPC patients suffer from hepatomegaly and progressive cognitive and locomotion losses, with massive Purkinje ..
  21. Mechanisms of Cell Death after Photodynamic Therapy
    Anna Liisa Nieminen; Fiscal Year: 2010
    ..However, PC 4 and a recently synthesized PC 4 derivative PC 181 also localize to endoplasmic reticulum (ER) and lysosomes. We hypothesize that damage to these organelles by PC 4 and PC 181 leads to additional perturbations, such as ..
  22. The role of two-pore channels in integrative calcium signaling
    Michael X Zhu; Fiscal Year: 2013
    ..NAADP response is abolished by disrupting proton gradient of lysosomes and RNAi-mediated silencing of TPC2 expression, as well as genetic ablation of the Tpc2 gene in mice...
  23. Role of Autophagy in Cancer
    Eileen White; Fiscal Year: 2013
    ..proteins and organelles by the process of macroautophagy (autophagy hereafter), which delivers them to lysosomes where they are degraded...
  24. CYTOSKELETAL REGULATION OF VESICLE TRANSPORT IN LIVER
    MARK A MC NIVEN; Fiscal Year: 2013
    ..in hepatocytes to mediate internalization and post-endocytic trafficking of the EGFR, targeting this receptor to lysosomes for degradation...
  25. Role of p62 in Protein Aggregation and Neurodegeneration in ALS
    Haining Zhu; Fiscal Year: 2009
    ..Purchase of necessary equipment, supplies and reagents for the proposed research will also stimulate the economy as intended by the American Recovery &Reinvestment Act. ..
  26. Gene Therapy of Mucopolysaccharidosis VII
    Mark E Haskins; Fiscal Year: 2012
    ..to other organs, was taken up via the M6P receptor on the plasma membrane of cells, and was trafficked to the lysosomes. Some blood cells were also transduced, which may have contributed to the therapeutic response...
  27. Functional consequences of autophagy mutations in Crohn's disease.
    David L Boone; Fiscal Year: 2012
    ..These studies will help us to understand how mutations implicated in Crohn's disease affect cell functions to contribute to inflammation. ..
  28. Disordered Cellular Cholesterol Movement, Cell Death, and Multisystem Disease
    STEPHEN DEAN TURLEY; Fiscal Year: 2013
    ....
  29. Physiology of Class III PI 3-kinase Signaling 2
    Jonathan M Backer; Fiscal Year: 2013
    ..Given that hVps34 is one of the key kinases involved in autophagy, a better understanding of its regulation will lead to new insights into this critical cellular process. ..
  30. The Lysosome of Trypanosoma brucei: A Proteomic Analysis
    James D Bangs; Fiscal Year: 2012
    ..Mammalian lysosomes contain ~75 proteins that have been validated by biochemical and/or proteomic analyses, and of these ~half are ..
  31. V-ATPase H+ PUMP REGULATION IN FUEL ENERGY SELECTION
    Karlett J Parra; Fiscal Year: 2013
    ..Located at the membrane of lysosomes, vacuoles and endosomes, V-ATPases sustain the acidic luminal pH needed for protein sorting and degradation;and ..
  32. Hypothalamic autophagy and metabolic regulation in aging
    Rajat Singh; Fiscal Year: 2013
    ..MA) is an essential mechanism that maintains cellular homeostasis by degrading proteins and organelles in lysosomes. Our published results have shown a role for MA in hypothalamic AgRP neurons in control of food intake...
  33. Gene Networks Regulating Muscle Protein Degradation
    Nathaniel J Szewczyk; Fiscal Year: 2010
    ..g., insulin, IGF-1, TNF-cc) and intramuscular enzymes that degrade proteins (e.g., proteasomes, calpains, lysosomes)...
  34. Mechanisms of Resistance and Susceptibility to African Trypanosome Infection
    Stephen L Hajduk; Fiscal Year: 2013
    ..This may allow us to develop novel approaches for the treatment of this important human disease. ..
  35. Receptor-mediated Endocytosis-Mechanism and Function
    Frederick R Maxfield; Fiscal Year: 2013
    ..Delivery of these proteins to late endosomes and lysosomes is essential for proper acidification of these organelles In microglial cells...
  36. Role of Ion Channel in Mononuclear Phagocyte Activation
    Deborah J Nelson; Fiscal Year: 2012
    ..b>Lysosomes and phagosomes in murine cftr/- AMs failed to acidify and the cells were deficient in bacterial killing compared ..
  37. Regulation of myocardial growth and death by autophagy
    Junichi Sadoshima; Fiscal Year: 2013
    ..PUBLIC HEALTH RELEVANCE: Autophagy, an important mechanism of protein degradation through lysosomes, plays an adaptive role in various pathophysiological conditions...
  38. Elevated Zinc in Ischemia and reperfusion
    Yang V Li; Fiscal Year: 2013
    ..the Zn2+ release from intracellular storages such as mitochondria, endoplasmic reticulum, Golgi apparatus and lysosomes. The release of Zn2+ from the storages may contribute to early Zn2+ accumulation and subsequent mitochondrial ..
  39. GM2 Gangliosidosis Therapy Using Neurotropic Enzyme
    Kostantin Dobrenis; Fiscal Year: 2010
    ..replacement (HSCRT) and gene replacement therapies variably rely on delivery of exogenous or secreted enzyme to lysosomes of host deficient neurons through endocytic uptake...
  40. Imaging and Function of the Immunological Synapse
    David C Parker; Fiscal Year: 2012
    ..vitro and in vivo, this proposal will test the hypothesis that pre-formed CD40L and FasL are stored in secretory lysosomes in most primed CD4 effector and memory T cells, are delivered rapidly through the immunological synapse to B ..
  41. Degradation of Endoplasmic Reticulum Chaperones by Chaperone-mediated Autophagy
    Roberta Kiffin; Fiscal Year: 2010
    ..for cellular quality control, as it is responsible for the elimination of altered intracellular components in lysosomes. Autophagy also contributes to the maintenance of cellular protein and organelle homeostasis...
  42. Molecular Mechanisms of Albumin Trafficking in Podocytes
    Judith T Blaine; Fiscal Year: 2013
    ....
  43. Function of metal transporter ZIP14 as regulated by proinflammatory stimuli
    Robert J Cousins; Fiscal Year: 2013
    ..ZIP8 mediated transport of Zn2+ from lysosomes of activated T cells maintains CREB in its phosphorylated forum enabling enhanced IFNy transcription...
  44. ApoE receptor pathways and abeta metabolism
    Guojun Bu; Fiscal Year: 2013
    ..heparan sulfate proteoglycan (HSPG) to mediate A[unreadable] uptake, trafficking and eventual delivery to lysosomes. Conditional knockout of Lrp1 in neurons in adult mice leads to increase A[unreadable] accumulation and amyloid ..
  45. Mechanisms of Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
    Lisa R Young; Fiscal Year: 2013
    ..Because type II cell dysfunction is a unifying feature of many fibrotic lung diseases, further study of HPS trafficking defects will likey elucidate mechanisms of pulmonary fibrosis with broad relevance. ..
  46. HLTF gene silencing: a novel determinant of sensitivity to autophagy inhibition
    Ravi K Amaravadi; Fiscal Year: 2013
    ....
  47. Activation of rapamycin-sensitive TORC1 by endomembrane amino acid transporters
    MARIA E CARDENAS-CORONA; Fiscal Year: 2013
    ..Similar to yeast TORC1, mammalian TORC1 is also localized to endomembranes, in particular lysosomes, which are the counterparts of yeast vacuoles...
  48. Endoplasmic reticulum quality control of mutant HexA enzyme in Tay-Sachs disease
    Devin Dersh; Fiscal Year: 2013
    ....
  49. Modulation of Rab7-Dependent Degradative Pathways by Novel Adenovirus Protein
    Cathleen R Carlin; Fiscal Year: 2012
    ..which was originally identified because of its ability to divert constitutively recycling EGF receptors to lysosomes. We have recently discovered that RID[unreadable] interacts with RILP and ORP1L, two known effectors for the ..
  50. EGF Receptor Signaling in Time and Space in Tumor Cells
    Alexander D Sorkin; Fiscal Year: 2012
    ..The activated EGFR is rapidly internalized into endosomes and sorted to lysosomes for degradation. There are numerous bi-directional cross-talks between signaling and endocytic machineries...
  51. Defining Mechanisms of TDP-43 Ubiquitination for Quality Control and Aggregation
    ERIC BERNARD DAMMER; Fiscal Year: 2012
    ....
  52. Pathophysiology of PPARgamma in the lung
    Hong Du; Fiscal Year: 2012
    ..of matrix metalloproteinase-12 (MMP-12) and that this control derives from fatty acid ligands, generated in the lysosomes by lysosomal acid lipase (LAL)...
  53. MICROTUBULE-BASED TRANSPORT IN LACRIMAL GLAND FUNCTION
    Sarah F Hamm-Alvarez; Fiscal Year: 2012
    ..the proteins destined for apical secretion via regulated exocytosis and the proteins destined to function in the lysosomes (Lys) follow the same biosynthetic pathway through the endoplasmic reticulum (ER) and Golgi complex to the TGN...
  54. FcgRIIb protects fetus from allograft rejection
    Clark L Anderson; Fiscal Year: 2013
    ..Endothelial cell lysosomes would not be essential and endothelial cells themselves would not be the site of degradation...
  55. A Role for Melanoregulin in RPE-mediated Phagocytosis
    KATHLEEN B BOESZE BATTAGLIA; Fiscal Year: 2010
    ..epithelial cells'(RPE)1 role as professional phagocytes is the regulated biogenesis and maturation of lysosomes which serves as the major degrading compartment, containing over 50 acid-dependent hydrolytic enzymes (1)...
  56. A High-throughput Screen of Lytic Granule Exocytosis
    Adam Zweifach; Fiscal Year: 2012
    ..If it can, we will use it to screen a large scale compound library for inhibitory compounds. ..
  57. A Phase 0 Trial of Hydroxychloroquine in Patients with Stage III and IV Resectabl
    Janice Mehnert; Fiscal Year: 2010
    ..Our hope is that we will be able to use these results to better understand and detect autophagy, making it easier to develop future drugs against this pathway in cancer. ..
  58. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..and lower LDL;4) elucidation of the hydrophobic handoff mechanism for export of LDL-derived cholesterol from lysosomes;5) delineation of the sterol-regulated, ubiquitin-mediated pathway for degradation of HMG CoA reductase and ..
  59. ROLE OF AUTOPHAGIC FLUX IN CARDIAC MYOCYTE VIABILITY
    Abhinav Diwan; Fiscal Year: 2013
    ..Strategies to facilitate autophagic flux, such as restoration of LAMP2A and B levels in lysosomes, could treat Danon disease and enable pro-survival outcomes with stress-induced activation of autophagic ..
  60. Molecular Mechanisims of Amylin Trafficking and Toxicity in Human Pancreatic Isle
    ALEKSANDAR MILORAD JEREMIC; Fiscal Year: 2013
    ..amylin receptor (AM-R), clathrin and v- SNARE/Rab endocytotic proteins mediate amylin uptake and degradation in lysosomes, the impairment of which stimulates amylin oligomerization and aggregation, oxidative stress and consequently ..
  61. The roles of acidic autophagosomes in production of infectious poliovirus
    William T Jackson; Fiscal Year: 2013
    ..We have found that vesicle acidification, which in the case of autophagosomes is required for fusion with lysosomes, is required for cleavage of a viral capsid protein, the final step in generating infectious virus from newly ..
  62. Self-complementary rAAV9 Systemic Gene Delivery Treatment for MPS Type IIIA
    Douglas M McCarty; Fiscal Year: 2013
    ..correct the pathology at the cellular level, leading to clearance of accumulated glycosaminoglycans (GAGs) in lysosomes. Because the neuropathology of MPS IIIA is global, affecting all areas of the brain, effective gene delivery to ..
  63. DIETARY & GENETIC CONTROL OF ROS DAMAGE TO THE LENS
    Norman S Wolf; Fiscal Year: 2010
    ..accumulates in ARC at both the Bow region and at abnormal interior sites- is there a debris removal failure of lysosomes and lysosomal enzyme activity? 4) Is the abnormal loss of LEC from the lens surface (a possible initiator of the ..
  64. AREA: Synthesis and Evaluation of New Cathepsin B, D, and K Inhibitors
    Rose McConnell; Fiscal Year: 2009
    ..Most assume cathepsins B, D, and K to be restricted to the lysosomes where they are involved in protein degradation...
  65. ON THE ROLE OF THE HPS GENE PRODUCT IN MELANOCYTES
    Raymond Boissy; Fiscal Year: 2002
    ..These studies will contribute to our knowledge of cellular trafficking in general and the pathophysiology of HPS in specific. ..
  66. A Phase l Study of Pyrimethamine in patients with GM-2 Gangliosidosis
    Bijan Almassian; Fiscal Year: 2007
    ..a disease model for TSD and SD which attributes pathology to decreased or absent Hex A levels in neuronal lysosomes of the brain. The problem in GM2-gangliosidosis is the inability of the cell to metabolize GM2 gangliosides...
  67. Role of BLOC-3 in Lysosome and Melanosome Biogenesis
    ESTEBAN DELL ANGELICA; Fiscal Year: 2007
    ..in the biogenesis of several types of related organelles, including melanosomes, platelet dense granules and lysosomes. The goal of this project is to elucidate the function(s) of the products of the HPS1 and HPS4 genes, which are ..
  68. METABOLISM AND FUNCTION IN THE AGING ADRENAL GLAND
    JEROME KOWAL; Fiscal Year: 1993
    ..The importance of mitochondria and lysosomes in the steroidogenic process points to an association between the observed morphological and functional changes ..
  69. INTRACELLULAR TRANSPORT PATHWAYS FOR PROCESSING ANTIGENS
    KATHLEEN MCCOY; Fiscal Year: 1993
    ..In receptor bearing cells, transferrin conjugates should be directed away from the lysosomes, whereas alpha 2-macroglobulin conjugates should be delivered to the lysosomes...
  70. LISTERIA MONOCYTOGENES AND PHAGOSOME MEMBRANE TRAFFIC
    Philip Stahl; Fiscal Year: 2003
    ..We will determine the effects of IFNgamma treatment on vesicular traffic into and out of LM phagosomes using GFP-Rab5, GFP-Rab7 and GFP-Rab11. ..
  71. MECHANISMS OF ENDOSOME TO LYSOSOME TRANSPORT IN YEAST
    Thomas Vida; Fiscal Year: 2005
    ..The greatest source of confusion about the PLC concerns whether carrier vesicles transport material to lysosomes or if the PLC undergoes a maturation process, changing into a lysosome...
  72. CHOLESTEROL AND NEURODEGENERATION
    Shutish Patel; Fiscal Year: 2001
    ..These NPC1 positive vesicles are clearly distinct from the cholesterol filled lysosomes that are a hallmark of NP-C cells...