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Cited by 200Lysosomal Storage Disorders ResearchBiomedical Research and PathophysiologyGlycogen Storage Diseases and Myoclonus

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

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Davis, Oliver B., Shin, Hijai R., Lim, Chun-Yan, Wu, Emma Y., Kukurugya, Matthew, Maher, Claire F., Perera, Rushika M., Ordonez, M. Paulina +1 more·2021·Developmental Cell
DOI 10.1016/j.devcel.2020.11.016PMC PMC8919971

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Abstract

Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.

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  • Cholesterol accumulation in lysosomes impairs lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.

    “Cholesterol accumulation in lysosomes has been shown to impair lysosomal functions, including autophagy-mediated mitochondrial degradation, in various pathological conditions, including Niemann-Pick disease type C.15”

    From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [16]

    The Introduction links lysosomal cholesterol accumulation in NPC1-deficient cells to lysosomal dysfunction, and the Results report impaired steps in mitophagy, the autophagic clearance of mitochondria (page numbers unavailable). The paper supports the claim for Niemann-Pick type C, but does not establish that cholesterol accumulation causes these effects across the various other pathological conditions claimed. (LLM, conf=0.86)

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Research works printed but not linked: 87

  1. Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, Freinkman E, and Sabatini DM (2017). Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807– 813. 29074583 PMC5704967
  2. Anandapadamanaban M, Masson GR, Perisic O, Berndt A, Kaufman J, Johnson CM, Santhanam B, Rogala KB, Sabatini DM, and Williams RL (2019). Architecture of human Rag GTPase heterodimers and their complex with mTORC1. Science 366, 203– 210. 31601764 PMC6795536
  3. Andrzejewska Z, Nevo N, Thomas L, Chhuon C, Bailleux A, Chauvet V, Courtoy PJ, Chol M, Guerrera IC, and Antignac C. (2016). Cystinosin is a Component of the Vacuolar H+-ATPase-Ragulator-Rag Complex Controlling Mammalian Target of Rapamycin Complex 1 Signaling. J. Am. Soc. Nephrol. 27, 1678– 1688. 26449607 PMC4884097
  4. Ballabio A, and Gieselmann V. (2009). Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793, 684– 696. 19111581
  5. Bartolomeo R, Cinque L, De Leonibus C, Forrester A, Salzano AC, Monfregola J, De Gennaro E, Nusco E, Azario I, Lanzara C, (2017). mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J. Clin. Invest. 127, 3717– 3729. 28872463 PMC5617676
  6. Brown RA, Voit A, Srikanth MP, Thayer JA, Kingsbury TJ, Jacobson MA, Lipinski MM, Feldman RA, and Awad O. (2019). mTOR hyperactivity mediates lysosomal dysfunction in Gaucher’s disease iPSC-neuronal cells. Dis Model Mech 12. PMC6826018 31519738
  7. Burgett AWG, Poulsen TB, Wangkanont K, Anderson DR, Kikuchi C, Shimada K, Okubo S, Fortner KC, Mimaki Y, Kuroda M, (2011). Natural products reveal cancer cell dependence on oxysterol-binding proteins. Nat. Chem. Biol. 7, 639– 647. 21822274 PMC3158287
  8. Calvo SE, Clauser KR, and Mootha VK (2016). MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44, D1251– 1257. 26450961 PMC4702768
  9. Chiaruttini N, Redondo-Morata L, Colom A, Humbert F, Lenz M, Scheuring S, and Roux A. (2015). Relaxation of Loaded ESCRT-III Spiral Springs Drives Membrane Deformation. Cell 163, 866– 879. 26522593 PMC4644223
  10. Chung C, Puthanveetil P, Ory DS, and Lieberman AP (2016). Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration. Hum. Mol. Genet. 25, 1434– 1446. 26908626 PMC4787909
  11. Chung CY-S, Shin HR, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R, and Nomura DK (2019). Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nat. Chem. Biol. 15, 776– 785. 31285595 PMC6641988
  12. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, and Puigserver P. (2007). mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450, 736– 740. 18046414
  13. Danyukova T, Ariunbat K, Thelen M, Brocke-Ahmadinejad N, Mole SE, and Storch S. (2018). Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation. Hum. Mol. Genet. 27, 1711– 1722. 29514215 PMC5932567
  14. Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, and De Camilli P. (2016). Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P. Cell 166, 408– 423. 27419871 PMC4963242
  15. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, (2010). Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171– 183. 20670887 PMC2946786
  16. Ebrahimi-Fakhari D, Saffari A, Wahlster L, Di Nardo A, Turner D, Lewis TL, Conrad C, Rothberg JM, Lipton JO, Kölker S, (2016). Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex. Cell Rep 17, 1053– 1070. 27760312 PMC5078873
  17. Elrick MJ, Yu T, Chung C, and Lieberman AP (2012). Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease. Hum. Mol. Genet. 21, 4876– 4887. 22872701 PMC3607480
  18. Feltes M, Gale SE, Moores S, Ory DS, and Schaffer JE (2020). Monitoring the itinerary of lysosomal cholesterol in Niemann-Pick Type C1-deficient cells after cyclodextrin treatment. J. Lipid Res. 61, 403– 412. 31988149 PMC7053843
  19. Gao Y, Zhou Y, Goldstein JL, Brown MS, and Radhakrishnan A. (2017). Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control cholesterol synthesis. J. Biol. Chem. 292, 8729– 8737. 28377508 PMC5448100
  20. Gong X, Qian H, Zhou X, Wu J, Wan T, Cao P, Huang W, Zhao X, Wang X, Wang P, (2016). Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection. Cell 165, 1467– 1478. 27238017 PMC7111323
  21. Hämälistö S, Stahl JL, Favaro E, Yang Q, Liu B, Christoffersen L, Loos B, Guasch Boldú C, Joyce JA, Reinheckel T, (2020). Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation. Nat Commun 11, 229. 31932607 PMC6957743
  22. Infante RE, and Radhakrishnan A. (2017). Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol. Elife 6. PMC5433840 28414269
  23. Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, and Goldstein JL (2008). NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc. Natl. Acad. Sci. U.S.A. 105, 15287– 15292. 18772377 PMC2563079
  24. Ivanova EA, van den Heuvel LP, Elmonem MA, De Smedt H, Missiaen L, Pastore A, Mekahli D, Bultynck G, and Levtchenko EN (2016). Altered mTOR signalling in nephropathic cystinosis. J. Inherit. Metab. Dis. 39, 457– 464. 26909499
  25. Jia J, Claude-Taupin A, Gu Y, Choi SW, Peters R, Bissa B, Mudd MH, Allers L, Pallikkuth S, Lidke KA, (2020). Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal. Dev. Cell 52, 69– 87.e8. 31813797 PMC6997950
  26. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, and Youle RJ (2010). Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933– 942. 21115803 PMC2995166
  27. Kane LA, Lazarou M, Fogel AI, Li Y, Yamano K, Sarraf SA, Banerjee S, and Youle RJ (2014). PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. J. Cell Biol. 205, 143– 153. 24751536 PMC4003245
  28. Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, and Muqit MMK (2014). Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65. Biochem. J. 460, 127– 139. 24660806 PMC4000136
  29. Kennedy BE, Madreiter CT, Vishnu N, Malli R, Graier WF, and Karten B. (2014). Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient cells. J. Biol. Chem. 289, 16278– 16289. 24790103 PMC4047397
  30. Khaminets A, Behl C, and Dikic I. (2016). Ubiquitin-Dependent And Independent Signals In Selective Autophagy. Trends Cell Biol. 26, 6– 16. 26437584
  31. Kim J, Kundu M, Viollet B, and Guan K-L (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132– 141. 21258367 PMC3987946
  32. Kobayashi T, Beuchat MH, Lindsay M, Frias S, Palmiter RD, Sakuraba H, Parton RG, and Gruenberg J. (1999). Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat. Cell Biol. 1, 113– 118. 10559883
  33. Kwon HJ, Abi-Mosleh L, Wang ML, Deisenhofer J, Goldstein JL, Brown MS, and Infante RE (2009). Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137, 1213– 1224. 19563754 PMC2739658
  34. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638– 1643. 22461615 PMC3324089
  35. Lawrence RE, and Zoncu R. (2019). The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133– 142. 30602725
  36. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, and Youle RJ (2015). The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309– 314. 26266977 PMC5018156
  37. Li X, Saha P, Li J, Blobel G, and Pfeffer SR (2016). Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proc. Natl. Acad. Sci. U.S.A. 113, 10079– 10084. 27551080 PMC5018801
  38. Lim C-Y, Davis OB, Shin HR, Zhang J, Berdan CA, Jiang X, Counihan JL, Ory DS, Nomura DK, and Zoncu R. (2019). ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C. Nat. Cell Biol. 21, 1206– 1218. 31548609 PMC6936960
  39. Liu GY, and Sabatini DM (2020). mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. PMC7102936 31937935
  40. Liu EA, Schultz ML, Mochida C, Chung C, Paulson HL, and Lieberman AP (2020). Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain. JCI Insight. PMC7605537 32931479
  41. Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, (1997). Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232– 235. 9211850
  42. Maekawa M, and Fairn GD (2015). Complementary probes reveal that phosphatidylserine is required for the proper transbilayer distribution of cholesterol. J. Cell. Sci. 128, 1422– 1433. 25663704
  43. Mahoney SJ, Narayan S, Molz L, Berstler LA, Kang SA, Vlasuk GP, and Saiah E. (2018). A small molecule inhibitor of Rheb selectively targets mTORC1 signaling. Nat Commun 9, 548. 29416044 PMC5803267
  44. Martina JA, Chen Y, Gucek M, and Puertollano R. (2012). MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903– 914. 22576015 PMC3427256
  45. Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, and Manning BD (2014). Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771– 785. 24529379 PMC4030681
  46. Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, and Antonny B. (2013). A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155, 830– 843. 24209621
  47. Millard EE, Gale SE, Dudley N, Zhang J, Schaffer JE, and Ory DS (2005). The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol. J. Biol. Chem. 280, 28581– 28590. 15908696
  48. Morita M, Prudent J, Basu K, Goyon V, Katsumura S, Hulea L, Pearl D, Siddiqui N, Strack S, McGuirk S, (2017). mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1. Mol. Cell 67, 922–935.e5. 28918902
  49. Nguyen HC, Talledge N, McCullough J, Sharma A, Moss FR, Iwasa JH, Vershinin MD, Sundquist WI, and Frost A. (2020). Membrane constriction and thinning by sequential ESCRT-III polymerization. Nat. Struct. Mol. Biol. 27, 392– 399. 32251413 PMC7343221
  50. Ordonez MP (2012). Defective mitophagy in human Niemann-Pick Type C1 neurons is due to abnormal autophagy activation. Autophagy 8, 1157– 1158. 22647841 PMC3429558
  51. Ordonez MP, Roberts EA, Kidwell CU, Yuan SH, Plaisted WC, and Goldstein LSB (2012). Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1. Hum. Mol. Genet. 21, 2651– 2662. 22437840 PMC3363339
  52. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong S-E, Walford GA, Sugiana C, Boneh A, Chen WK, (2008). A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112– 123. 18614015 PMC2778844
  53. Perera RM, and Zoncu R. (2016). The Lysosome as a Regulatory Hub. Annu. Rev. Cell Dev. Biol. 32, 223– 253. 27501449 PMC9345128
  54. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, (2011). mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146, 408– 420. 21816276 PMC3336367
  55. Pfeffer SR (2019). NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes. J. Biol. Chem. 294, 1706– 1709. 30710017 PMC6364775
  56. Platt FM, d’Azzo A, Davidson BL, Neufeld EF, and Tifft CJ (2018). Lysosomal storage diseases. Nat Rev Dis Primers 4, 27. 30275469
  57. Puente C, Hendrickson RC, and Jiang X. (2016). Nutrient-regulated Phosphorylation of ATG13 Inhibits Starvation-induced Autophagy. J. Biol. Chem. 291, 6026– 6035. 26801615 PMC4786734
  58. Radulovic M, Schink KO, Wenzel EM, Nähse V, Bongiovanni A, Lafont F, and Stenmark H. (2018). ESCRT-mediated lysosome repair precedes lysophagy and promotes cell survival. EMBO J. 37. PMC6213280 30314966
  59. Repnik U, Česen MH, and Turk B. (2016). The Use of Lysosomotropic Dyes to Exclude Lysosomal Membrane Permeabilization. Cold Spring Harb Protoc 2016. 27140914
  60. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, and Ferguson SM (2012). The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 5, ra42. PMC3437338 22692423
  61. Rogala KB, Gu X, Kedir JF, Abu-Remaileh M, Bianchi LF, Bottino AMS, Dueholm R, Niehaus A, Overwijn D, Fils A-CP, (2019). Structural basis for the docking of mTORC1 on the lysosomal surface. Science 366, 468– 475. 31601708 PMC7176403
  62. Saftig P, and Klumperman J. (2009). Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat. Rev. Mol. Cell Biol. 10, 623– 635. 19672277
  63. Sakamachi Y, Morioka S, Mihaly SR, Takaesu G, Foley JF, Fessler MB, and Ninomiya-Tsuji J. (2017). TAK1 regulates resident macrophages by protecting lysosomal integrity. Cell Death Dis 8, e2598. PMC5386472 28182011
  64. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, (2009). A gene network regulating lysosomal biogenesis and function. Science 325, 473– 477. 19556463
  65. Sarkar S, Carroll B, Buganim Y, Maetzel D, Ng AHM, Cassady JP, Cohen MA, Chakraborty S, Wang H, Spooner E, (2013). Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep 5, 1302– 1315. 24290752 PMC3957429
  66. Schedin S, Sindelar PJ, Pentchev P, Brunk U, and Dallner G. (1997). Peroxisomal impairment in Niemann-Pick type C disease. J. Biol. Chem. 272, 6245– 6251. 9045641
  67. Schöneberg J, Lee I-H, Iwasa JH, and Hurley JH (2017). Reverse-topology membrane scission by the ESCRT proteins. Nat. Rev. Mol. Cell Biol. 18, 5– 17. 27703243 PMC5198518
  68. Schreiber KH, Arriola Apelo SI, Yu D, Brinkman JA, Velarde MC, Syed FA, Liao C-Y, Baar EL, Carbajal KA, Sherman DS, (2019). A novel rapamycin analog is highly selective for mTORC1 in vivo. Nat Commun 10, 3194. 31324799 PMC6642166
  69. Schultz ML, Krus KL, Kaushik S, Dang D, Chopra R, Qi L, Shakkottai VG, Cuervo AM, and Lieberman AP (2018). Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. Nat Commun 9, 3671. 30202070 PMC6131187
  70. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, (2012). A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095– 1108. 22343943 PMC3298007
  71. Skowyra ML, Schlesinger PH, Naismith TV, and Hanson PI (2018). Triggered recruitment of ESCRT machinery promotes endolysosomal repair. Science 360. PMC6195421 29622626
  72. Sleat DE, Sun P, Wiseman JA, Huang L, El-Banna M, Zheng H, Moore DF, and Lobel P. (2013). Extending the mannose 6-phosphate glycoproteome by high resolution/accuracy mass spectrometry analysis of control and acid phosphatase 5-deficient mice. Mol. Cell Proteomics 12, 1806– 1817. 23478313 PMC3708167
  73. Su M-Y, Morris KL, Kim DJ, Fu Y, Lawrence R, Stjepanovic G, Zoncu R, and Hurley JH (2017). Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. Mol. Cell 68, 835–846.e3. PMC5722659 29107538
  74. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, and Gray NS (2009). An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023– 8032. 19150980 PMC2658096
  75. Toulmay A, and Prinz WA (2013). Direct imaging reveals stable, micrometer-scale lipid domains that segregate proteins in live cells. J. Cell Biol. 202, 35– 44. 23836928 PMC3704982
  76. Tsuji T, Fujimoto M, Tatematsu T, Cheng J, Orii M, Takatori S, and Fujimoto T. (2017). Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole. Elife 6. PMC5462540 28590904
  77. Walkley SU, and Suzuki K. (2004). Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim. Biophys. Acta 1685, 48– 62. 15465426
  78. Wang S, Tsun Z-Y, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, (2015). Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188– 194. 25567906 PMC4295826
  79. Wauer T, Simicek M, Schubert A, and Komander D. (2015). Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature 524, 370– 374. 26161729 PMC4984986
  80. Weber RA, Yen FS, Nicholson SPV, Alwaseem H, Bayraktar EC, Alam M, Timson RC, La K, Abu-Remaileh M, Molina H, (2020). Maintaining Iron Homeostasis Is the Key Role of Lysosomal Acidity for Cell Proliferation. Mol. Cell 77, 645–655.e7. PMC7176020 31983508
  81. Winkler MBL, Kidmose RT, Szomek M, Thaysen K, Rawson S, Muench SP, Wüstner D, and Pedersen BP (2019). Structural Insight into Eukaryotic Sterol Transport through Niemann-Pick Type C Proteins. Cell 179, 485–497.e18. 31543266
  82. Wyant GA, Abu-Remaileh M, Wolfson RL, Chen WW, Freinkman E, Danai LV, Vander Heiden MG, and Sabatini DM (2017). mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell 171, 642–654.e12. PMC5704964 29053970
  83. Yabe D, Xia Z-P, Adams CM, and Rawson RB (2002). Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. Proc. Natl. Acad. Sci. U.S.A. 99, 16672– 16677. 12482938 PMC139202
  84. Yambire KF, Fernandez-Mosquera L, Steinfeld R, Mühle C, Ikonen E, Milosevic I, and Raimundo N. (2019a). Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases. Elife 8. PMC6379092 30775969
  85. Yambire KF, Rostosky C, Watanabe T, Pacheu-Grau D, Torres-Odio S, Sanchez-Guerrero A, Senderovich O, Meyron-Holtz EG, Milosevic I, Frahm J, (2019b). Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo. Elife 8. PMC6917501 31793879
  86. Yu W, Gong J-S, Ko M, Garver WS, Yanagisawa K, and Michikawa M. (2005). Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. J. Biol. Chem. 280, 11731– 11739. 15644330
  87. Yuan SH, Martin J, Elia J, Flippin J, Paramban RI, Hefferan MP, Vidal JG, Mu Y, Killian RL, Israel MA, (2011). Cell-surface marker signatures for the isolation of neural stem cells, glia and neurons derived from human pluripotent stem cells. PLoS ONE 6, e17540. PMC3047583 21407814

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Authors
Davis, O. B., Shin, H. R., Lim, C.-Y., Wu, E. Y., Kukurugya, M., Maher, C. F., Perera, R. M., Ordonez, M. P., & Zoncu, R.
Affiliations
  • University of California, Berkeley (US)
  • University of California San Diego (US)
  • University of California, San Francisco (US)
Corresponding author
  • Ordonez, M. Paulina
  • Zoncu, Roberto
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2021-02
Volume
56
Issue
3
Pages
260-276.e7
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2020.11.016
PMC
PMC8919971
OpenAlex
W3111564394
Cited by
200
References
14
Citations by year
2026: 29 · 2025: 37 · 2024: 42 · 2023: 36 · 2022: 41 · 2021: 15
FWCI
13.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Biomedical Research and Pathophysiology
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords
Niemann-Pick disease type C, NPC1, mTORC1, lysosomal cholesterol, lysosomal proteolysis, mitophagy, mitochondrial dysfunction, lysosomal membrane damage, mTORC1 inhibition, cholesterol sensing, neurodegeneration
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Niemann-Pick C1 Protein, Adult, Animals, Cells, Cultured, Cholesterol, Homeostasis, Humans, Intracellular Membranes, Lysosomes, Mitochondria, Models, Biological, Neurons, Organelles, Signal Transduction, Intracellular Signaling Peptides and Proteins, Mice, Niemann-Pick Disease, Type C, Induced Pluripotent Stem Cells, HEK293 Cells, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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