1932

Abstract

The lysosome has long been viewed as the recycling center of the cell. However, recent discoveries have challenged this simple view and have established a central role of the lysosome in nutrient-dependent signal transduction. The degradative role of the lysosome and its newly discovered signaling functions are not in conflict but rather cooperate extensively to mediate fundamental cellular activities such as nutrient sensing, metabolic adaptation, and quality control of proteins and organelles. Moreover, lysosome-based signaling and degradation are subject to reciprocal regulation. Transcriptional programs of increasing complexity control the biogenesis, composition, and abundance of lysosomes and fine-tune their activity to match the evolving needs of the cell. Alterations in these essential activities are, not surprisingly, central to the pathophysiology of an ever-expanding spectrum of conditions, including storage disorders, neurodegenerative diseases, and cancer. Thus, unraveling the functions of this fascinating organelle will contribute to our understanding of the fundamental logic of metabolic organization and will point to novel therapeutic avenues in several human diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cellbio-111315-125125
2016-10-06
2024-06-13
Loading full text...

Full text loading...

/deliver/fulltext/cellbio/32/1/annurev-cellbio-111315-125125.html?itemId=/content/journals/10.1146/annurev-cellbio-111315-125125&mimeType=html&fmt=ahah

Literature Cited

  1. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. 2004. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N. Engl. J. Med. 351:1972–77 [Google Scholar]
  2. Aits S, Jaattela M. 2013. Lysosomal cell death at a glance. J. Cell Sci. 126:1905–12 [Google Scholar]
  3. Baba M, Takeshige K, Baba N, Ohsumi Y. 1994. Ultrastructural analysis of the autophagic process in yeast: detection of autophagosomes and their characterization. J. Cell Biol. 124:903–13 [Google Scholar]
  4. Ballabio A, Gieselmann V. 2009. Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793:684–96 [Google Scholar]
  5. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA. et al. 2013. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340:1100–6 [Google Scholar]
  6. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. 2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150:1196–208 [Google Scholar]
  7. Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH. 2014. Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 10:1415–25 [Google Scholar]
  8. Bellettato CM, Scarpa M. 2010. Pathophysiology of neuropathic lysosomal storage disorders. J. Inherit. Metab. Dis. 33:347–62 [Google Scholar]
  9. Ben-Sahra I, Hoxhaj G, Ricoult SJ, Asara JM, Manning BD. 2016. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351:728–33 [Google Scholar]
  10. Binda M, Peli-Gulli MP, Bonfils G, Panchaud N, Urban J. et al. 2009. The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35:563–73 [Google Scholar]
  11. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M. et al. 2005. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171:603–14 [Google Scholar]
  12. Bowman CJ, Ayer DE, Dynlacht BD. 2014. Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat. Cell Biol. 16:1202–14 [Google Scholar]
  13. Budanov AV, Karin M. 2008. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–60 [Google Scholar]
  14. Bultron G, Kacena K, Pearson D, Boxer M, Yang R. et al. 2010. The risk of Parkinson's disease in type 1 Gaucher disease. J. Inherit. Metab. Dis. 33:167–73 [Google Scholar]
  15. Burkhardt JK, Echeverri CJ, Nilsson T, Vallee RB. 1997. Overexpression of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-dependent maintenance of membrane organelle distribution. J. Cell Biol. 139:469–84 [Google Scholar]
  16. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K. et al. 2013. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152:778–90 [Google Scholar]
  17. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D. et al. 1997. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–31 [Google Scholar]
  18. Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K. et al. 2016. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165:153–64 [Google Scholar]
  19. Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM. et al. 2014. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep 9:1–8 [Google Scholar]
  20. Chantranupong L, Wolfson RL, Sabatini DM. 2015. Nutrient-sensing mechanisms across evolution. Cell 161:67–83 [Google Scholar]
  21. Chapel A, Kieffer-Jaquinod S, Sagne C, Verdon Q, Ivaldi C. et al. 2013. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol. Cell. Proteom. 12:1572–88 [Google Scholar]
  22. Chauhan S, Goodwin JG, Chauhan S, Manyam G, Wang J. et al. 2013. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol. Cell 50:16–28 [Google Scholar]
  23. Cheng X, Zhang X, Gao Q, Ali Samie M, Azar M. et al. 2014. The intracellular Ca2+ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy. Nat. Med. 20:1187–92 [Google Scholar]
  24. Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M. et al. 2007. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448:68–72 [Google Scholar]
  25. Chu BB, Liao YC, Qi W, Xie C, Du X. et al. 2015. Cholesterol transport through lysosome-peroxisome membrane contacts. Cell 161:291–306 [Google Scholar]
  26. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ. et al. 2013. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497:633–37 [Google Scholar]
  27. Conner SD, Schmid SL. 2003. Regulated portals of entry into the cell. Nature 422:37–44 [Google Scholar]
  28. Cox TM, Cachon-Gonzalez MB. 2012. The cellular pathology of lysosomal diseases. J. Pathol. 226:241–54 [Google Scholar]
  29. Davidson SM, Papagiannakopoulos T, Olenchock BA, Heyman JE, Keibler MA. et al. 2016. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab 23:517–28 [Google Scholar]
  30. Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA. et al. 2003. Cloning of an α-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation. PNAS 100:6051–56 [Google Scholar]
  31. de Duve C. 2005. The lysosome turns fifty. Nat. Cell Biol. 7:847–49 [Google Scholar]
  32. de Duve C, Wattiaux R. 1966. Functions of lysosomes. Annu. Rev. Physiol. 28:435–92 [Google Scholar]
  33. Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A. 2013. TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. PNAS 110:E1817–26 [Google Scholar]
  34. Demetriades C, Doumpas N, Teleman AA. 2014. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156:786–99 [Google Scholar]
  35. DeNicola GM, Cantley LC. 2015. Cancer's fuel choice: new flavors for a picky eater. Mol. Cell 60:514–23 [Google Scholar]
  36. Deretic V, Levine B. 2009. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5:527–49 [Google Scholar]
  37. Di Fiore PP, von Zastrow M. 2014. Endocytosis, signaling, and beyond. Cold Spring Harb. Perspect. Biol. 6:a016865 [Google Scholar]
  38. Di Paolo G, De Camilli P. 2006. Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–57 [Google Scholar]
  39. Diao J, Liu R, Rong Y, Zhao M, Zhang J. et al. 2015. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520:563–66 [Google Scholar]
  40. Dokudovskaya S, Waharte F, Schlessinger A, Pieper U, Devos DP. et al. 2011. A conserved coatomer-related complex containing Sec 13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae. Mol. Cell. Proteom. 10:M110.06478 [Google Scholar]
  41. Dong XP, Cheng X, Mills E, Delling M, Wang F. et al. 2008. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–96 [Google Scholar]
  42. Dubouloz F, Deloche O, Wanke V, Cameroni E, De Virgilio C. 2005. The TOR and EGO protein complexes orchestrate microautophagy in yeast. Mol. Cell 19:15–26 [Google Scholar]
  43. Durr KL, Chen L, Stein RA, De Zorzi R, Folea IM. et al. 2014. Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states. Cell 158:778–92 [Google Scholar]
  44. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI. et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39:171–83 [Google Scholar]
  45. Dyer CM, Vartanian AS, Zhou H, Dahlquist FW. 2009. A molecular mechanism of bacterial flagellar motor switching. J. Mol. Biol. 388:71–84 [Google Scholar]
  46. Efe JA, Botelho RJ, Emr SD. 2005. The Fab1 phosphatidylinositol kinase pathway in the regulation of vacuole morphology. Curr. Opin. Cell Biol. 17:402–8 [Google Scholar]
  47. Efeyan A, Zoncu R, Sabatini DM. 2012. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18:524–33 [Google Scholar]
  48. Egan D, Kim J, Shaw RJ, Guan KL. 2011. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:643–44 [Google Scholar]
  49. Elbaz-Alon Y, Rosenfeld-Gur E, Shinder V, Futerman AH, Geiger T, Schuldiner M. 2014. A dynamic interface between vacuoles and mitochondria in yeast. Dev. Cell 30:95–102 [Google Scholar]
  50. Farquhar MG, Bainton DF, Baggiolini M, de Duve C. 1972. Cytochemical localization of acid phosphatase activity in granule fractions from rabbit polymorphonuclear leukocytes. J. Cell Biol. 54:141–56 [Google Scholar]
  51. Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerod L. et al. 2007. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179:485–500 [Google Scholar]
  52. Folick A, Oakley HD, Yu Y, Armstrong EH, Kumari M. et al. 2015. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347:83–86 [Google Scholar]
  53. Forgac M. 2007. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 8:917–29 [Google Scholar]
  54. Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ. et al. 2005. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436:117–22 [Google Scholar]
  55. Ge L, Baskaran S, Schekman R, Hurley JH. 2014. The protein-vesicle network of autophagy. Curr. Opin. Cell Biol. 29:18–24 [Google Scholar]
  56. Goker-Alpan O, Lopez G, Vithayathil J, Davis J, Hallett M, Sidransky E. 2008. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch. Neurol. 65:1353–57 [Google Scholar]
  57. Goldstein JL, Brown MS. 2015. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161:161–72 [Google Scholar]
  58. Goodwin ML, Jin H, Straessler K, Smith-Fry K, Zhu JF. et al. 2014. Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment. Cancer Cell 26:851–62 [Google Scholar]
  59. Guo B, Liang Q, Li L, Hu Z, Wu F. et al. 2014. O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nat. Cell Biol. 16:1215–26 [Google Scholar]
  60. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM. et al. 2011. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 25:460–70 [Google Scholar]
  61. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. 2004. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753–66 [Google Scholar]
  62. Haq R, Fisher DE. 2011. Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. J. Clin. Oncol. 29:3474–82 [Google Scholar]
  63. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y. et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–89 [Google Scholar]
  64. Harada A, Takei Y, Kanai Y, Tanaka Y, Nonaka S, Hirokawa N. 1998. Golgi vesiculation and lysosome dispersion in cells lacking cytoplasmic dynein. J. Cell Biol. 141:51–59 [Google Scholar]
  65. He C, Klionsky DJ. 2009. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43:67–93 [Google Scholar]
  66. Henne WM, Buchkovich NJ, Emr SD. 2011. The ESCRT pathway. Dev. Cell 21:77–91 [Google Scholar]
  67. Honscher C, Mari M, Auffarth K, Bohnert M, Griffith J. et al. 2014. Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev. Cell 30:86–94 [Google Scholar]
  68. Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A. et al. 2009. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell 20:1981–91 [Google Scholar]
  69. Hurley JH, Schulman BA. 2014. Atomistic autophagy: the structures of cellular self-digestion. Cell 157:300–11 [Google Scholar]
  70. Inoki K, Li Y, Xu T, Guan KL. 2003. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–34 [Google Scholar]
  71. Ishida Y, Nayak S, Mindell JA, Grabe M. 2013. A model of lysosomal pH regulation. J. Gen. Physiol. 141:705–20 [Google Scholar]
  72. Itakura E, Kishi-Itakura C, Mizushima N. 2012. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256–69 [Google Scholar]
  73. Jewell JL, Kim YC, Russell RC, Yu FX, Park HW. et al. 2015. Differential regulation of mTORC1 by leucine and glutamine. Science 347:194–98 [Google Scholar]
  74. Jeyakumar M, Dwek RA, Butters TD, Platt FM. 2005. Storage solutions: treating lysosomal disorders of the brain. Nat. Rev. Neurosci. 6:713–25 [Google Scholar]
  75. Jezegou A, Llinares E, Anne C, Kieffer-Jaquinod S, O'Regan S. et al. 2012. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. PNAS 109:E3434–43 [Google Scholar]
  76. Johnson DE, Ostrowski P, Jaumouille V, Grinstein S. 2016. The position of lysosomes within the cell determines their luminal pH. J. Cell Biol. 212:677–92 [Google Scholar]
  77. Jones CB, Ott EM, Keener JM, Curtiss M, Sandrin V, Babst M. 2012. Regulation of membrane protein degradation by starvation-response pathways. Traffic 13:468–82 [Google Scholar]
  78. Jung J, Genau HM, Behrends C. 2015. Amino acid–dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol. Cell. Biol. 35:2479–94 [Google Scholar]
  79. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. 2000. Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150:1507–13 [Google Scholar]
  80. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R. et al. 2013. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. PNAS 110:8882–87 [Google Scholar]
  81. Kamphorst JJ, Nofal M, Commisso C, Hackett SR, Lu W. et al. 2015. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75:544–53 [Google Scholar]
  82. Karsli-Uzunbas G, Guo JY, Price S, Teng X, Laddha SV. et al. 2014. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 4:914–27 [Google Scholar]
  83. Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ. et al. 2014. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat. Rev. Urol. 11:465–75 [Google Scholar]
  84. Kaur J, Debnath J. 2015. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16:461–72 [Google Scholar]
  85. Kaushik S, Cuervo AM. 2012. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 22:407–17 [Google Scholar]
  86. Kenzelmann Broz D, Spano Mello S, Bieging KT, Jiang D, Dusek RL. et al. 2013. Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev 27:1016–31 [Google Scholar]
  87. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10:935–45 [Google Scholar]
  88. Kitamoto K, Yoshizawa K, Ohsumi Y, Anraku Y. 1988. Dynamic aspects of vacuolar and cytosolic amino acid pools of Saccharomyces cerevisiae. J. Bacteriol. 170:2683–86 [Google Scholar]
  89. Klumperman J, Raposo G. 2014. The complex ultrastructure of the endolysosomal system. Cold Spring Harb. Perspect. Biol. 6:a016857 [Google Scholar]
  90. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J. et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84 [Google Scholar]
  91. Kornfeld S, Mellman I. 1989. The biogenesis of lysosomes. Annu. Rev. Cell Biol. 5:483–525 [Google Scholar]
  92. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA. et al. 2011. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13:453–60 [Google Scholar]
  93. Kraft C, Peter M. 2008. Is the Rsp5 ubiquitin ligase involved in the regulation of ribophagy. ? Autophagy 4:838–40 [Google Scholar]
  94. Kroemer G. 2015. Autophagy: a druggable process that is deregulated in aging and human disease. J. Clin. Investig. 125:1–4 [Google Scholar]
  95. Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E. et al. 2003. Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution. Hum. Mol. Genet. 12:1661–69 [Google Scholar]
  96. Kummel D, Ungermann C. 2014. Principles of membrane tethering and fusion in endosome and lysosome biogenesis. Curr. Opin. Cell Biol. 29:61–66 [Google Scholar]
  97. Kwon HJ, Abi-Mosleh L, Wang ML, Deisenhofer J, Goldstein JL. et al. 2009. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137:1213–24 [Google Scholar]
  98. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A. et al. 2001. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to. ASPL , a novel gene at 17q25. Oncogene 20:48–57 [Google Scholar]
  99. Lapierre LR, Kumsta C, Sandri M, Ballabio A, Hansen M. 2015. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11:867–80 [Google Scholar]
  100. Laplante M, Sabatini DM. 2012. mTOR signaling in growth control and disease. Cell 149:274–93 [Google Scholar]
  101. Lazarou M, Jin SM, Kane LA, Youle RJ. 2012. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin. Dev. Cell 22:320–33 [Google Scholar]
  102. Lee JM, Wagner M, Xiao R, Kim KH, Feng D. et al. 2014. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–15 [Google Scholar]
  103. Li SC, Kane PM. 2009. The yeast lysosome-like vacuole: endpoint and crossroads. Biochim. Biophys. Acta 1793:650–63 [Google Scholar]
  104. Li X, Rydzewski N, Hider A, Zhang X, Yang J. et al. 2016. A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat. Cell Biol. 8:404–17 [Google Scholar]
  105. Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A. 2012. Autophagy in lysosomal storage disorders. Autophagy 8:719–30 [Google Scholar]
  106. Lin CH, MacGurn JA, Chu T, Stefan CJ, Emr SD. 2008. Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface. Cell 135:714–25 [Google Scholar]
  107. Liu B, Du H, Rutkowski R, Gartner A, Wang X. 2012. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337:351–54 [Google Scholar]
  108. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E. et al. 2008. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14:1247–55 [Google Scholar]
  109. Lock R, Roy S, Kenific CM, Su JS, Salas E. et al. 2011. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol. Biol. Cell 22:165–78 [Google Scholar]
  110. Lunt SY, Vander Heiden MG. 2011. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27:441–64 [Google Scholar]
  111. Luzio JP, Pryor PR, Bright NA. 2007. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 8:622–32 [Google Scholar]
  112. Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G. et al. 2014. Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma. J. Clin. Investig. 124:1406–17 [Google Scholar]
  113. Ma XM, Blenis J. 2009. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10:307–18 [Google Scholar]
  114. MacGurn JA, Hsu PC, Smolka MB, Emr SD. 2011. TORC1 regulates endocytosis via Npr1-mediated phosphoinhibition of a ubiquitin ligase adaptor. Cell 147:1104–17 [Google Scholar]
  115. Maejima I, Takahashi A, Omori H, Kimura T, Takabatake Y. et al. 2013. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J 32:2336–47 [Google Scholar]
  116. Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi RK. et al. 2014. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 10:1403–14 [Google Scholar]
  117. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R. et al. 2007. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–71 [Google Scholar]
  118. Marchand B, Arsenault D, Raymond-Fleury A, Boisvert FM, Boucher MJ. 2015. Glycogen synthase kinase-3 (GSK3) inhibition induces prosurvival autophagic signals in human pancreatic cancer cells. J. Biol. Chem. 290:5592–605 [Google Scholar]
  119. Marks MS, Heijnen HF, Raposo G. 2013. Lysosome-related organelles: Unusual compartments become mainstream. Curr. Opin. Cell Biol. 25:495–505 [Google Scholar]
  120. Martina JA, Chen Y, Gucek M, Puertollano R. 2012. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8:903–14 [Google Scholar]
  121. Martina JA, Puertollano R. 2013. Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes. J. Cell Biol. 200:475–91 [Google Scholar]
  122. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ. et al. 2011. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37–52 [Google Scholar]
  123. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH. et al. 2012. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. PNAS 109:8253–58 [Google Scholar]
  124. McCullough J, Clippinger AK, Talledge N, Skowyra ML, Saunders MG. et al. 2015. Structure and membrane remodeling activity of ESCRT-III helical polymers. Science 350:1548–51 [Google Scholar]
  125. McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H. et al. 2015. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol. Cell 57:39–54 [Google Scholar]
  126. Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D. et al. 2015. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat. Cell Biol. 17:288–99 [Google Scholar]
  127. Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G. et al. 2011. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21:421–30 [Google Scholar]
  128. Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ. et al. 2014. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771–85 [Google Scholar]
  129. Metcalf DJ, Garcia-Arencibia M, Hochfeld WE, Rubinsztein DC. 2012. Autophagy and misfolded proteins in neurodegeneration. Exp. Neurol. 238:22–28 [Google Scholar]
  130. Mindell JA. 2012. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74:69–86 [Google Scholar]
  131. Mizushima N, Komatsu M. 2011. Autophagy: renovation of cells and tissues. Cell 147:728–41 [Google Scholar]
  132. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 2008. Autophagy fights disease through cellular self-digestion. Nature 451:1069–75 [Google Scholar]
  133. Mochida K, Oikawa Y, Kimura Y, Kirisako H, Hirano H. et al. 2015. Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. Nature 522:359–62 [Google Scholar]
  134. Muller M, Schmidt O, Angelova M, Faserl K, Weys S. et al. 2015. The coordinated action of the MVB pathway and autophagy ensures cell survival during starvation. eLife 4:e07736 [Google Scholar]
  135. Nada S, Hondo A, Kasai A, Koike M, Saito K. et al. 2009. The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. EMBO J 28:477–89 [Google Scholar]
  136. Nakata T, Hirokawa N. 1995. Point mutation of adenosine triphosphate–binding motif generated rigor kinesin that selectively blocks anterograde lysosome membrane transport. J. Cell Biol. 131:1039–53 [Google Scholar]
  137. Neudorfer O, Giladi N, Elstein D, Abrahamov A, Turezkite T. et al. 1996. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 89:691–94 [Google Scholar]
  138. Nixon RA. 2013. The role of autophagy in neurodegenerative disease. Nat. Med. 19:983–97 [Google Scholar]
  139. Noda T, Ohsumi Y. 1998. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273:3963–66 [Google Scholar]
  140. Novikoff AB, Beaufay H, de Duve C. 1956. Electron microscopy of lysosomerich fractions from rat liver. J. Biophys. Biochem. Cytol. 2:179–84 [Google Scholar]
  141. Nylandsted J, Gyrd-Hansen M, Danielewicz A, Fehrenbacher N, Lademann U. et al. 2004. Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J. Exp. Med. 200:425–35 [Google Scholar]
  142. O'Rourke EJ, Ruvkun G. 2013. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15:668–76 [Google Scholar]
  143. Ohya T, Miaczynska M, Coskun U, Lommer B, Runge A. et al. 2009. Reconstitution of Rab- and SNARE-dependent membrane fusion by synthetic endosomes. Nature 459:1091–97 [Google Scholar]
  144. Osellame LD, Rahim AA, Hargreaves IP, Gegg ME, Richard-Londt A. et al. 2013. Mitochondria and quality control defects in a mouse model of Gaucher disease—links to Parkinson's disease. Cell Metab 17:941–53 [Google Scholar]
  145. Ottemann KM, Xiao W, Shin YK, Koshland DE Jr. 1999. A piston model for transmembrane signaling of the aspartate receptor. Science 285:1751–54 [Google Scholar]
  146. Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB. 2015. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 162:259–70 [Google Scholar]
  147. Palmieri M, Impey S, Kang H, di Ronza A, Pelz C. et al. 2011. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20:3852–66 [Google Scholar]
  148. Panchaud N, Peli-Gulli MP, De Virgilio C. 2013. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6:ra42 [Google Scholar]
  149. Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC. et al. 2014. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9:1281–91 [Google Scholar]
  150. Peli-Gulli MP, Sardu A, Panchaud N, Raucci S, De Virgilio C. 2015. Amino acids stimulate TORC1 through Lst4-Lst7, a GTPase-activating protein complex for the Rag family GTPase Gtr2. Cell Rep 13:1–7 [Google Scholar]
  151. Perera RM, Bardeesy N. 2015. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov 5:1247–61 [Google Scholar]
  152. Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J. et al. 2015. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524:361–65 [Google Scholar]
  153. Petersen NH, Olsen OD, Groth-Pedersen L, Ellegaard AM, Bilgin M. et al. 2013. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell 24:379–93 [Google Scholar]
  154. Petit CS, Roczniak-Ferguson A, Ferguson SM. 2013. Recruitment of folliculin to lysosomes supports the amino acid–dependent activation of Rag GTPases. J. Cell Biol. 202:1107–22 [Google Scholar]
  155. Piao S, Amaravadi RK. 2016. Targeting the lysosome in cancer. Ann. N. Y. Acad. Sci. 1371:45–54 [Google Scholar]
  156. Pike LR, Singleton DC, Buffa F, Abramczyk O, Phadwal K. et al. 2013. Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival. Biochem. J. 449:389–400 [Google Scholar]
  157. Platt FM. 2014. Sphingolipid lysosomal storage disorders. Nature 510:68–75 [Google Scholar]
  158. Platt FM, Boland B, van der Spoel AC. 2012. Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 199:723–34 [Google Scholar]
  159. Ploper D, Taelman VF, Robert L, Perez BS, Titz B. et al. 2015. MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells. PNAS 112:E420–29 [Google Scholar]
  160. Polishchuk EV, Concilli M, Iacobacci S, Chesi G, Pastore N. et al. 2014. Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Dev. Cell 29:686–700 [Google Scholar]
  161. Pu J, Schindler C, Jia R, Jarnik M, Backlund P, Bonifacino JS. 2015. BORC, a multisubunit complex that regulates lysosome positioning. Dev. Cell 33:176–88 [Google Scholar]
  162. Rabinowitz JD, White E. 2010. Autophagy and metabolism. Science 330:1344–48 [Google Scholar]
  163. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D. et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:1184–91 [Google Scholar]
  164. Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M. et al. 2014. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5:3056 [Google Scholar]
  165. Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C. et al. 2005. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nat. Genet. 37:771–76 [Google Scholar]
  166. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S. et al. 2004. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36:585–95 [Google Scholar]
  167. Rebsamen M, Pochini L, Stasyk T, de Araujo ME, Galluccio M. et al. 2015. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519:477–81 [Google Scholar]
  168. Reddy A, Caler EV, Andrews NW. 2001. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106:157–69 [Google Scholar]
  169. Rink J, Ghigo E, Kalaidzidis Y, Zerial M. 2005. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122:735–49 [Google Scholar]
  170. Rocha N, Kuijl C, van der Kant R, Janssen L, Houben D. et al. 2009. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7-RILP-p150 Glued and late endosome positioning. J. Cell Biol. 185:1209–25 [Google Scholar]
  171. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J. et al. 2012. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5:ra42 [Google Scholar]
  172. Rodriguez-Navarro JA, Kaushik S, Koga H, Dall'Armi C, Shui G. et al. 2012. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. PNAS 109:E705–14 [Google Scholar]
  173. Rong Y, Liu M, Ma L, Du W, Zhang H. et al. 2012. Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation. Nat. Cell Biol. 14:924–34 [Google Scholar]
  174. Rong Y, McPhee CK, Deng S, Huang L, Chen L. et al. 2011. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. PNAS 108:7826–31 [Google Scholar]
  175. Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J. et al. 2010. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J. Clin. Investig 120:127–41 [Google Scholar]
  176. Russnak R, Konczal D, McIntire SL. 2001. A family of yeast proteins mediating bidirectional vacuolar amino acid transport. J. Biol. Chem. 276:23849–57 [Google Scholar]
  177. Saftig P, Klumperman J. 2009. Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function. Nat. Rev. Mol. Cell Biol. 10:623–35 [Google Scholar]
  178. Sagne C, Agulhon C, Ravassard P, Darmon M, Hamon M. et al. 2001. Identification and characterization of a lysosomal transporter for small neutral amino acids. PNAS 98:7206–11 [Google Scholar]
  179. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B. et al. 2011. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20:131–39 [Google Scholar]
  180. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303 [Google Scholar]
  181. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC. et al. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–501 [Google Scholar]
  182. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M. et al. 2009. A gene network regulating lysosomal biogenesis and function. Science 325:473–77 [Google Scholar]
  183. Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME. et al. 2016. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351:53–58 [Google Scholar]
  184. Schroder B, Wrocklage C, Pan C, Jager R, Kosters B. et al. 2007. Integral and associated lysosomal membrane proteins. Traffic 8:1676–86 [Google Scholar]
  185. Sekito T, Fujiki Y, Ohsumi Y, Kakinuma Y. 2008. Novel families of vacuolar amino acid transporters. IUBMB Life 60:519–25 [Google Scholar]
  186. Seok S, Fu T, Choi SE, Li Y, Zhu R. et al. 2014. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516:108–11 [Google Scholar]
  187. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F. et al. 2013a. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15:647–58 [Google Scholar]
  188. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F. et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 [Google Scholar]
  189. Settembre C, Fraldi A, Jahreiss L, Spampanato C, Venturi C. et al. 2008. A block of autophagy in lysosomal storage disorders. Hum. Mol. Genet. 17:119–29 [Google Scholar]
  190. Settembre C, Fraldi A, Medina DL, Ballabio A. 2013b. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14:283–96 [Google Scholar]
  191. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S. et al. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31:1095–108 [Google Scholar]
  192. Shang L, Chen S, Du F, Li S, Zhao L, Wang X. 2011. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. PNAS 108:4788–93 [Google Scholar]
  193. Shen HM, Mizushima N. 2014. At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy. Trends Biochem. Sci. 39:61–71 [Google Scholar]
  194. Singh R, Cuervo AM. 2011. Autophagy in the cellular energetic balance. Cell Metab 13:495–504 [Google Scholar]
  195. Skibinski G, Parkinson NJ, Brown JM, Chakrabarti L, Lloyd SL. et al. 2005. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37:806–8 [Google Scholar]
  196. Sleat DE, Sun P, Wiseman JA, Huang L, El-Banna M. et al. 2013. Extending the mannose 6-phosphate glycoproteome by high resolution/accuracy mass spectrometry analysis of control and acid phosphatase 5-deficient mice. Mol. Cell. Proteom. 12:1806–17 [Google Scholar]
  197. Song W, Wang F, Savini M, Ake A, di Ronza A. et al. 2013. TFEB regulates lysosomal proteostasis. Hum. Mol. Genet. 22:1994–2009 [Google Scholar]
  198. Sorkin A, von Zastrow M. 2009. Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol. 10:609–22 [Google Scholar]
  199. Spampanato C, Feeney E, Li L, Cardone M, Lim JA. et al. 2013. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol. Med. 5:691–706 [Google Scholar]
  200. Spinosa MR, Progida C, De Luca A, Colucci AM, Alifano P, Bucci C. 2008. Functional characterization of Rab7 mutant proteins associated with Charcot-Marie-Tooth type 2B disease. J. Neurosci. 28:1640–48 [Google Scholar]
  201. Steinberg BE, Huynh KK, Brodovitch A, Jabs S, Stauber T. et al. 2010. A cation counterflux supports lysosomal acidification. J. Cell Biol. 189:1171–86 [Google Scholar]
  202. Stinchcombe JC, Griffiths GM. 2007. Secretory mechanisms in cell-mediated cytotoxicity. Annu. Rev. Cell Dev. Biol. 23:495–517 [Google Scholar]
  203. Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ. et al. 2013. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov 3:1272–85 [Google Scholar]
  204. Sui X, Chen R, Wang Z, Huang Z, Kong N. et al. 2013. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis 4:e838 [Google Scholar]
  205. Tayebi N, Walker J, Stubblefield B, Orvisky E, LaMarca ME. et al. 2003. Gaucher disease with parkinsonian manifestations: Does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism. ? Mol. Genet. Metab. 79:104–9 [Google Scholar]
  206. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13:1259–68 [Google Scholar]
  207. Teis D, Wunderlich W, Huber LA. 2002. Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev. Cell 3:803–14 [Google Scholar]
  208. Tsun Z-Y, Bar-Peled L, Chantranupong L, Zoncu R, Wang T. et al. 2013. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52:495–50 [Google Scholar]
  209. Vergarajauregui S, Puertollano R. 2008. Mucolipidosis type IV: the importance of functional lysosomes for efficient autophagy. Autophagy 4:832–34 [Google Scholar]
  210. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N. et al. 2014. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514:628–32 [Google Scholar]
  211. Vogl DT, Stadtmauer EA, Tan KS, Heitjan DF, Davis LE. et al. 2014. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 10:1380–90 [Google Scholar]
  212. Wang S, Tsun Z-Y, Wolfson RL, Shen K, Wyant GA. et al. 2015. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347:188–94 [Google Scholar]
  213. Wang W, Gao Q, Yang M, Zhang X, Yu L. et al. 2015. Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. PNAS 112:E1373–81 [Google Scholar]
  214. Wang X, Zhang X, Dong XP, Samie M, Li X. et al. 2012. TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell 151:372–83 [Google Scholar]
  215. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T. et al. 2013. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494:323–27 [Google Scholar]
  216. Watson RO, Manzanillo PS, Cox JS. 2012. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150:803–15 [Google Scholar]
  217. Watts C. 2012. The endosome-lysosome pathway and information generation in the immune system. Biochim. Biophys. Acta 1824:14–21 [Google Scholar]
  218. Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL. 2011. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 25:1510–27 [Google Scholar]
  219. White E. 2015. The role for autophagy in cancer. J. Clin. Investig. 125:42–46 [Google Scholar]
  220. Wiemken A, Durr M. 1974. Characterization of amino acid pools in the vacuolar compartment of Saccharomyces cerevisiae. Arch. Microbiol. 101:45–57 [Google Scholar]
  221. Wild P, McEwan DG, Dikic I. 2014. The LC3 interactome at a glance. J. Cell Sci. 127:3–9 [Google Scholar]
  222. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM. et al. 2016. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351:43–48 [Google Scholar]
  223. Wollert T, Hurley JH. 2010. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 464:864–69 [Google Scholar]
  224. Wolpin BM, Rubinson DA, Wang X, Chan JA, Cleary JM. et al. 2014. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19:637–38 [Google Scholar]
  225. Wu B, Ottow K, Poulsen P, Gaber RF, Albers E, Kielland-Brandt MC. 2006. Competitive intra- and extracellular nutrient sensing by the transporter homologue Ssy1p. J. Cell Biol. 173:327–31 [Google Scholar]
  226. Wullschleger S, Loewith R, Hall MN. 2006. TOR signaling in growth and metabolism. Cell 124:471–84 [Google Scholar]
  227. Xie X, Koh JY, Price S, White E, Mehnert JM. 2015. Atg7 overcomes senescence and promotes growth of BrafV600E-driven melanoma. Cancer Discov 5:410–23 [Google Scholar]
  228. Xu H, Ren D. 2015. Lysosomal physiology. Annu. Rev. Physiol. 77:57–80 [Google Scholar]
  229. Xu S, Benoff B, Liou HL, Lobel P, Stock AM. 2007. Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease. J. Biol. Chem. 282:23525–31 [Google Scholar]
  230. Yang S, Wang X, Contino G, Liesa M, Sahin E. et al. 2011. Pancreatic cancers require autophagy for tumor growth. Genes Dev 25:717–29 [Google Scholar]
  231. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y. et al. 2010. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–46 [Google Scholar]
  232. Zhang C, Cuervo AM. 2008. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14:959–65 [Google Scholar]
  233. Zhang CS, Jiang B, Li M, Zhu M, Peng Y. et al. 2014. The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Cell Metab 20:526–40 [Google Scholar]
  234. Zhao J, Benlekbir S, Rubinstein JL. 2015. Electron cryomicroscopy observation of rotational states in a eukaryotic V-ATPase. Nature 521:241–45 [Google Scholar]
  235. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. 2011a. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334:678–83 [Google Scholar]
  236. Zoncu R, Efeyan A, Sabatini DM. 2011b. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:21–35 [Google Scholar]
  237. Zoncu R, Perera RM, Balkin DM, Pirruccello M, Toomre D, De Camilli P. 2009. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 136:1110–21 [Google Scholar]
/content/journals/10.1146/annurev-cellbio-111315-125125
Loading
/content/journals/10.1146/annurev-cellbio-111315-125125
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error