Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells[S]

In specialized cell types, lysosome-related organelles support regulated secretory pathways, whereas in nonspecialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol-storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in nonspecialized cells and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel mucolipin-1, as well as FYCO1, the AP1 adaptor, and its partner Gadkin. We conclude that endo-lysosomes in nonspecialized cells can acquire secretory functions elicited by cyclodextrin and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

[1]  Lauren C. Boudewyn,et al.  Current concepts in the neuropathogenesis of mucolipidosis type IV , 2018, Journal of neurochemistry.

[2]  J. Schulz,et al.  FYCO1 mediates clearance of α‐synuclein aggregates through a Rab7‐dependent mechanism , 2018, Journal of neurochemistry.

[3]  Kimberly A. Walters,et al.  Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial , 2017, The Lancet.

[4]  C. Austin,et al.  Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK , 2017, Autophagy.

[5]  A. Radhakrishnan,et al.  Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol , 2017, eLife.

[6]  R. Schiffmann,et al.  BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases , 2016, Scientific Reports.

[7]  G. Blobel,et al.  Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2 , 2016, Proceedings of the National Academy of Sciences.

[8]  J. Ramalho,et al.  A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair , 2016, The Journal of cell biology.

[9]  G. Gao,et al.  Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection , 2016, Cell.

[10]  E. Ikonen,et al.  LDL–cholesterol transport to the endoplasmic reticulum: current concepts , 2016, Current opinion in lipidology.

[11]  N. Guex,et al.  Wnt directs the endosomal flux of LDL‐derived cholesterol and lipid droplet homeostasis , 2015, EMBO reports.

[12]  M. Patterson,et al.  Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study , 2015, Orphanet Journal of Rare Diseases.

[13]  J. Bonifacino,et al.  BORC, a multisubunit complex that regulates lysosome positioning. , 2015, Developmental cell.

[14]  C. Bucci,et al.  Repeated ER–endosome contacts promote endosome translocation and neurite outgrowth , 2015, Nature.

[15]  C. Vite,et al.  Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease , 2015, Science Translational Medicine.

[16]  M. Corrotte,et al.  Damage control: cellular mechanisms of plasma membrane repair. , 2014, Trends in cell biology.

[17]  J. Luzio,et al.  The biogenesis of lysosomes and lysosome-related organelles. , 2014, Cold Spring Harbor perspectives in biology.

[18]  J. Vance,et al.  Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin , 2014, Journal of Lipid Research.

[19]  D. Ory,et al.  Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF , 2014, Journal of Lipid Research.

[20]  C. Vite,et al.  Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann-Pick C1 (NPC1). , 2014, Human molecular genetics.

[21]  Haoxing Xu,et al.  Lysosomal exocytosis and lipid storage disorders , 2014, Journal of Lipid Research.

[22]  J. Martina,et al.  The Nutrient-Responsive Transcription Factor TFE3 Promotes Autophagy, Lysosomal Biogenesis, and Clearance of Cellular Debris , 2014, Science Signaling.

[23]  N. B. Viana,et al.  Membrane Cholesterol Removal Changes Mechanical Properties of Cells and Induces Secretion of a Specific Pool of Lysosomes , 2013, PloS one.

[24]  S. Leppla,et al.  Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin. , 2013, Cell reports.

[25]  E. Ikonen,et al.  LDL cholesterol recycles to the plasma membrane via a Rab8a-Myosin5b-actin-dependent membrane transport route. , 2013, Developmental cell.

[26]  David A. Scott,et al.  Genome engineering using the CRISPR-Cas9 system , 2013, Nature Protocols.

[27]  M. Fukuda.  Rab27 Effectors, Pleiotropic Regulators in Secretory Pathways , 2013, Traffic.

[28]  G. Raposo,et al.  Lysosome-related organelles: unusual compartments become mainstream. , 2013, Current opinion in cell biology.

[29]  R. Parton,et al.  PNPLA3/adiponutrin functions in lipid droplet formation , 2013, Biology of the cell.

[30]  Christopher P Austin,et al.  δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders* , 2012, The Journal of Biological Chemistry.

[31]  H. Riezman,et al.  Glycosylphosphatidylinositol anchors regulate glycosphingolipid levels[S] , 2012, Journal of Lipid Research.

[32]  S. Munro,et al.  Arl8 and SKIP Act Together to Link Lysosomes to Kinesin-1 , 2011, Developmental cell.

[33]  A. Ballabio,et al.  Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance , 2011, Developmental cell.

[34]  T. Maritzen,et al.  Role of AP1 and Gadkin in the traffic of secretory endo-lysosomes , 2011, Molecular biology of the cell.

[35]  F. Maxfield,et al.  Niemann‐Pick type C disease: molecular mechanisms and potential therapeutic approaches , 2011, Journal of neurochemistry.

[36]  Gerhard G. Thallinger,et al.  Lipid Data Analyzer: unattended identification and quantitation of lipids in LC-MS data , 2011, Bioinform..

[37]  Y. Ioannou,et al.  Cyclodextrin Induces Calcium-Dependent Lysosomal Exocytosis , 2010, PloS one.

[38]  Joseph L. Goldstein,et al.  Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. , 2010, Cell metabolism.

[39]  J. Repa,et al.  Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid , 2010, Journal of Lipid Research.

[40]  F. Maxfield,et al.  Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells , 2010, Proceedings of the National Academy of Sciences.

[41]  G. Bjørkøy,et al.  FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end–directed vesicle transport , 2010, The Journal of cell biology.

[42]  J. Goldstein,et al.  Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells , 2009, Proceedings of the National Academy of Sciences.

[43]  D. Ory,et al.  Chronic Cyclodextrin Treatment of Murine Niemann-Pick C Disease Ameliorates Neuronal Cholesterol and Glycosphingolipid Storage and Disease Progression , 2009, PloS one.

[44]  Xian-Ping Dong,et al.  Activating Mutations of the TRPML1 Channel Revealed by Proline-scanning Mutagenesis* , 2009, The Journal of Biological Chemistry.

[45]  W. Zwart,et al.  Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning , 2009, The Journal of cell biology.

[46]  Joseph L. Goldstein,et al.  Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol , 2009, Cell.

[47]  J. Repa,et al.  Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse , 2009, Proceedings of the National Academy of Sciences.

[48]  Hongyuan Yang,et al.  Different kinetics of cholesterol delivery to components of the cholesterol homeostatic machinery: implications for cholesterol trafficking to the endoplasmic reticulum. , 2008, Biochimica et biophysica acta.

[49]  G. Prestwich,et al.  Lysobisphosphatidic Acid Controls Endosomal Cholesterol Levels* , 2008, Journal of Biological Chemistry.

[50]  Lisa N Kinch,et al.  Purified NPC1 Protein , 2008, Journal of Biological Chemistry.

[51]  E. Morel,et al.  The p11/S100A10 Light Chain of Annexin A2 Is Dispensable for Annexin A2 Association to Endosomes and Functions in Endosomal Transport , 2007, PloS one.

[52]  Ann M Stock,et al.  Structural Basis of Sterol Binding by NPC2, a Lysosomal Protein Deficient in Niemann-Pick Type C2 Disease* , 2007, Journal of Biological Chemistry.

[53]  F. G. van der Goot,et al.  Diversity of Raft-Like Domains in Late Endosomes , 2007, PloS one.

[54]  E. Brown,et al.  Lysosomal exocytosis is impaired in mucolipidosis type IV. , 2006, Molecular genetics and metabolism.

[55]  T. Steck,et al.  How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[56]  M. Vanier.  Niemann-Pick disease type C , 2010, Orphanet journal of rare diseases.

[57]  P. Cosson,et al.  Separation and Characterization of Late Endosomal Membrane Domains* , 2002, The Journal of Biological Chemistry.

[58]  M. Vidal,et al.  The exosome pathway in K562 cells is regulated by Rab11. , 2002, Journal of cell science.

[59]  F. Camargo,et al.  Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. , 2001, Life sciences.

[60]  E. Caler,et al.  Plasma Membrane Repair Is Mediated by Ca2+-Regulated Exocytosis of Lysosomes , 2001, Cell.

[61]  R. Wattiaux,et al.  Identification of HE1 as the second gene of Niemann-Pick C disease. , 2000, Science.

[62]  K. Simons,et al.  Jamming the endosomal system: lipid rafts and lysosomal storage diseases. , 2000, Trends in cell biology.

[63]  S. Matile,et al.  Rapid access to synthetic lysobisphosphatidic acids using P(III) chemistry. , 2000, Organic letters.

[64]  L. Liscum.  Niemann–Pick Type C Mutations Cause Lipid Traffic Jam , 2000, Traffic.

[65]  D. M. Amundson,et al.  Fluorometric method for the enzymatic determination of cholesterol. , 1999, Journal of biochemical and biophysical methods.

[66]  R. Parton,et al.  A lipid associated with the antiphospholipid syndrome regulates endosome structure and function , 1998, Nature.

[67]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[68]  H. Du,et al.  Characterization of Lysosomal Acid Lipase by Site-directed Mutagenesis and Heterologous Expression (*) , 1995, Journal of Biological Chemistry.

[69]  G. Griffiths,et al.  Cytoplasmic dynein-dependent vesicular transport from early to late endosomes [published erratum appears in J Cell Biol 1994 Feb;124(3):397] , 1993, The Journal of cell biology.

[70]  L. Liscum,et al.  Low density lipoprotein (LDL)-mediated suppression of cholesterol synthesis and LDL uptake is defective in Niemann-Pick type C fibroblasts. , 1987, The Journal of biological chemistry.

[71]  R. Brady,et al.  A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[72]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[73]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[74]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.

[75]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.

[76]  Miguel C. Seabra,et al.  1 Rab 27 a and Rab 27 b control different steps of the exosome secretion pathway , 2009 .

[77]  R. Palmiter,et al.  Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport , 1999, Nature Cell Biology.

[78]  I. Mellman,et al.  The biogenesis of lysosomes. , 1989, Annual review of cell biology.