Lysosomes are acidic compartments filled with more than 60 different types of hydrolases. They mediate the degradation of extracellular particles from endocytosis and of intracellular components from autophagy. The digested products are transported out of the lysosome via specific catabolite exporters or via vesicular membrane trafficking. Lysosomes also contain more than 50 membrane proteins and are equipped with the machinery to sense nutrient availability, which determines the distribution, number, size, and activity of lysosomes to control the specificity of cargo flux and timing (the initiation and termination) of degradation. Defects in degradation, export, or trafficking result in lysosomal dysfunction and lysosomal storage diseases (LSDs). Lysosomal channels and transporters mediate ion flux across perimeter membranes to regulate lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing. Dysregulation of lysosomal channels underlies the pathogenesis of many LSDs and possibly that of metabolic and common neurodegenerative diseases.


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Literature Cited

  1. Huotari J, Helenius A. 1.  2011. Endosome maturation. EMBO J. 30:3481–500 [Google Scholar]
  2. Luzio JP, Pryor PR, Bright NA. 2.  2007. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 8:622–32 [Google Scholar]
  3. Kolter T, Sandhoff K. 3.  2005. Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu. Rev. Cell Dev. Biol. 21:81–103 [Google Scholar]
  4. Ruivo R, Anne C, Sagne C, Gasnier B. 4.  2009. Molecular and cellular basis of lysosomal transmembrane protein dysfunction. Biochim. Biophys. Acta 1793:636–49 [Google Scholar]
  5. Saftig P, Klumperman J. 5.  2009. Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function. Nat. Rev. Mol. Cell Biol. 10:623–35 [Google Scholar]
  6. Settembre C, Fraldi A, Medina DL, Ballabio A. 6.  2013. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14:283–96 [Google Scholar]
  7. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y. 7.  et al. 2010. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465:942–46 [Google Scholar]
  8. Rong Y, McPhee CK, Deng S, Huang L, Chen L. 8.  et al. 2011. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc. Natl. Acad. Sci. USA 108:7826–31 [Google Scholar]
  9. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F. 9.  et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 [Google Scholar]
  10. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. 10.  2011. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334:678–83 [Google Scholar]
  11. Zhou J, Tan SH, Nicolas V, Bauvy C, Yang ND. 11.  et al. 2013. Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion. Cell Res. 23:508–23 [Google Scholar]
  12. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA. 12.  et al. 2011. Lysosomal positioning coordinates cellular nutrient responses. Nat. Cell Biol. 13:453–60 [Google Scholar]
  13. Mellman I. 13.  1989. Organelles observed: lysosomes. Science 244:853–54 [Google Scholar]
  14. Bandyopadhyay D, Cyphersmith A, Zapata JA, Kim YJ, Payne CK. 14.  2014. Lysosome transport as a function of lysosome diameter. PLOS ONE 9:e86847 [Google Scholar]
  15. Ohkuma S, Moriyama Y, Takano T. 15.  1983. Electrogenic nature of lysosomal proton pump as revealed with a cyanine dye. J. Biochem. 94:1935–43 [Google Scholar]
  16. Steinberg BE, Huynh KK, Brodovitch A, Jabs S, Stauber T. 16.  et al. 2010. A cation counterflux supports lysosomal acidification. J. Cell Biol. 189:1171–86 [Google Scholar]
  17. Ishida Y, Nayak S, Mindell JA, Grabe M. 17.  2013. A model of lysosomal pH regulation. J. Gen. Physiol. 141:705–20 [Google Scholar]
  18. Morgan AJ, Platt FM, Lloyd-Evans E, Galione A. 18.  2011. Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem. J. 439:349–74 [Google Scholar]
  19. Pisoni RL, Thoene JG. 19.  1991. The transport systems of mammalian lysosomes. Biochim. Biophys. Acta 1071:351–73 [Google Scholar]
  20. Dickson EJ, Duman JG, Moody MW, Chen L, Hille B. 20.  2012. Orai-STIM-mediated Ca2+ release from secretory granules revealed by a targeted Ca2+ and pH probe. Proc. Natl. Acad. Sci. USA 109:E3539–48 [Google Scholar]
  21. Jezegou A, Llinares E, Anne C, Kieffer-Jaquinod S, O'Regan S. 21.  et al. 2012. Heptahelical protein PQLC2 is a lysosomal cationic amino acid exporter underlying the action of cysteamine in cystinosis therapy. Proc. Natl. Acad. Sci. USA 109:E3434–43 [Google Scholar]
  22. Stauber T, Jentsch TJ. 22.  2013. Chloride in vesicular trafficking and function. Annu. Rev. Physiol. 75:453–77 [Google Scholar]
  23. Wang X, Zhang X, Dong XP, Samie M, Li X. 23.  et al. 2012. TPC proteins are phosphoinositide-activated sodium-selective ion channels in endosomes and lysosomes. Cell 151:372–83 [Google Scholar]
  24. Shen D, Wang X, Li X, Zhang X, Yao Z. 24.  et al. 2012. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat. Commun. 3:731 [Google Scholar]
  25. Luzio JP, Bright NA, Pryor PR. 25.  2007. The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Biochem. Soc. Trans. 35:1088–91 [Google Scholar]
  26. Li X, Garrity AG, Xu H. 26.  2013. Regulation of membrane trafficking by signalling on endosomal and lysosomal membranes. J. Physiol. 591:4389–401 [Google Scholar]
  27. Slaugenhaupt SA. 27.  2002. The molecular basis of mucolipidosis type IV. Curr. Mol. Med. 2:445–50 [Google Scholar]
  28. Mindell JA. 28.  2012. Lysosomal acidification mechanisms. Annu. Rev. Physiol. 74:69–86 [Google Scholar]
  29. Cang C, Zhou Y, Navarro B, Seo YJ, Aranda K. 29.  et al. 2013. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152:778–90 [Google Scholar]
  30. Dong XP, Wang X, Xu H. 30.  2010. TRP channels of intracellular membranes. J. Neurochem. 113:313–28 [Google Scholar]
  31. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E. 31.  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]
  32. Christensen KA, Myers JT, Swanson JA. 32.  2002. pH-dependent regulation of lysosomal calcium in macrophages. J. Cell Sci. 115:599–607 [Google Scholar]
  33. Pryor PR, Mullock BM, Bright NA, Gray SR, Luzio JP. 33.  2000. The role of intraorganellar Ca2+ in late endosome-lysosome heterotypic fusion and in the reformation of lysosomes from hybrid organelles. J. Cell Biol. 149:1053–62 [Google Scholar]
  34. Samie M, Wang X, Zhang X, Goschka A, Li X. 34.  et al. 2013. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev. Cell 26:511–24 [Google Scholar]
  35. Czibener C, Sherer NM, Becker SM, Pypaert M, Hui E. 35.  et al. 2006. Ca2+ and synaptotagmin VII–dependent delivery of lysosomal membrane to nascent phagosomes. J. Cell Biol. 174:997–1007 [Google Scholar]
  36. Vergarajauregui S, Martina JA, Puertollano R. 36.  2009. Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1. J. Biol. Chem. 284:36357–66 [Google Scholar]
  37. Chapman ER. 37.  2008. How does synaptotagmin trigger neurotransmitter release?. Annu. Rev. Biochem. 77:615–41 [Google Scholar]
  38. Kiselyov K, Colletti GA, Terwilliger A, Ketchum K, Lyons CW. 38.  et al. 2011. TRPML: transporters of metals in lysosomes essential for cell survival?. Cell Calcium 50:288–94 [Google Scholar]
  39. Mills E, Dong XP, Wang F, Xu H. 39.  2010. Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Future Med. Chem. 2:51 [Google Scholar]
  40. Schissel SL, Keesler GA, Schuchman EH, Williams KJ, Tabas I. 40.  1998. The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J. Biol. Chem. 273:18250–59 [Google Scholar]
  41. Lockwood TD. 41.  2013. Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction. Metallomics 5:110–24 [Google Scholar]
  42. DeFelice LJ, Goswami T. 42.  2007. Transporters as channels. Annu. Rev. Physiol. 69:87–112 [Google Scholar]
  43. Saito M, Hanson PI, Schlesinger P. 43.  2007. Luminal chloride–dependent activation of endosome calcium channels: patch clamp study of enlarged endosomes. J. Biol. Chem. 282:27327–33 [Google Scholar]
  44. Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A. 44.  2012. Autophagy in lysosomal storage disorders. Autophagy 8:719–30 [Google Scholar]
  45. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 45.  2008. Autophagy fights disease through cellular self-digestion. Nature 451:1069–75 [Google Scholar]
  46. Berg TO, Fengsrud M, Stromhaug PE, Berg T, Seglen PO. 46.  1998. Isolation and characterization of rat liver amphisomes. Evidence for fusion of autophagosomes with both early and late endosomes. J. Biol. Chem. 273:21883–92 [Google Scholar]
  47. Samie MA, Xu H. 47.  2014. Lysosomal exocytosis and lipid storage disorders. J. Lipid Res. 55:995–1009 [Google Scholar]
  48. Reddy A, Caler EV, Andrews NW. 48.  2001. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106:157–69 [Google Scholar]
  49. Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G. 49.  et al. 2011. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell 21:421–30 [Google Scholar]
  50. Rao SK, Huynh C, Proux-Gillardeaux V, Galli T, Andrews NW. 50.  2004. Identification of SNAREs involved in synaptotagmin VII–regulated lysosomal exocytosis. J. Biol. Chem. 279:20471–79 [Google Scholar]
  51. Sagne C, Gasnier B. 51.  2008. Molecular physiology and pathophysiology of lysosomal membrane transporters. J. Inherit. Metab. Dis. 31:258–66 [Google Scholar]
  52. Kalatzis V, Cherqui S, Antignac C, Gasnier B. 52.  2001. Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter. EMBO J. 20:5940–49 [Google Scholar]
  53. Liu B, Du H, Rutkowski R, Gartner A, Wang X. 53.  2012. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science 337:351–54 [Google Scholar]
  54. Ogmundsdottir MH, Heublein S, Kazi S, Reynolds B, Visvalingam SM. 54.  et al. 2012. Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLOS ONE 7:e36616 [Google Scholar]
  55. Dong XP, Cheng X, Mills E, Delling M, Wang F. 55.  et al. 2008. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455:992–96 [Google Scholar]
  56. Kukic I, Lee JK, Coblentz J, Kelleher SL, Kiselyov K. 56.  2013. Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. Biochem. J. 451:155–63 [Google Scholar]
  57. Eichelsdoerfer JL, Evans JA, Slaugenhaupt SA, Cuajungco MP. 57.  2010. Zinc dyshomeostasis is linked with the loss of mucolipidosis IV–associated TRPML1 ion channel. J. Biol. Chem. 285:34304–8 [Google Scholar]
  58. Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL. 58.  2008. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc. Natl. Acad. Sci. USA 105:15287–92 [Google Scholar]
  59. Vitner EB, Platt FM, Futerman AH. 59.  2010. Common and uncommon pathogenic cascades in lysosomal storage diseases. J. Biol. Chem. 285:20423–27 [Google Scholar]
  60. Schulze H, Sandhoff K. 60.  2011. Lysosomal lipid storage diseases. Cold Spring Harb. Perspect. Biol. 3:a004804 [Google Scholar]
  61. Parkinson-Lawrence EJ, Shandala T, Prodoehl M, Plew R, Borlace GN, Brooks DA. 61.  2010. Lysosomal storage disease: revealing lysosomal function and physiology. Physiology 25:102–15 [Google Scholar]
  62. Walkley SU, Vanier MT. 62.  2009. Secondary lipid accumulation in lysosomal disease. Biochim. Biophys. Acta 1793:726–36 [Google Scholar]
  63. Ballabio A, Gieselmann V. 63.  2009. Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793:684–96 [Google Scholar]
  64. Cang C, Bekele B, Ren D. 64.  2014. The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat. Chem. Biol. 10:463–69 [Google Scholar]
  65. Benjamin D, Hall MN. 65.  2014. mTORC1: Turning off is just as important as turning on. Cell 156:627–28 [Google Scholar]
  66. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. 66.  2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150:1196–208 [Google Scholar]
  67. Venugopal B, Browning MF, Curcio-Morelli C, Varro A, Michaud N. 67.  et al. 2007. Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am. J. Hum. Genet. 81:1070–83 [Google Scholar]
  68. Dong XP, Shen D, Wang X, Dawson T, Li X. 68.  et al. 2010. PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome. Nat. Commun. 1:38 [Google Scholar]
  69. Harikumar P, Reeves JP. 69.  1983. The lysosomal proton pump is electrogenic. J. Biol. Chem. 258:10403–10 [Google Scholar]
  70. Sasaki M, Takagi M, Okamura Y. 70.  2006. A voltage sensor-domain protein is a voltage-gated proton channel. Science 312:589–92 [Google Scholar]
  71. Ramsey IS, Delling M, Clapham DE. 71.  2006. An introduction to TRP channels. Annu. Rev. Physiol. 68:619–47 [Google Scholar]
  72. Graves AR, Curran PK, Smith CL, Mindell JA. 72.  2008. The Cl/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 453:788–92 [Google Scholar]
  73. Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. 73.  2011. ClC-7 is a slowly voltage-gated 2Cl/1H+-exchanger and requires Ostm1 for transport activity. EMBO J. 30:2140–52 [Google Scholar]
  74. Hodgkin AL. 74.  1958. Ionic movements and electrical activity in giant nerve fibres. Proc. R. Soc. B 148:1–37 [Google Scholar]
  75. Colletti GA, Kiselyov K. 75.  2011. Trpml1. Adv. Exp. Med. Biol. 704:209–19 [Google Scholar]
  76. Schieder M, Rotzer K, Bruggemann A, Biel M, Wahl-Schott C. 76.  2010. Planar patch clamp approach to characterize ionic currents from intact lysosomes. Sci. Signal. 3:pl3 [Google Scholar]
  77. Rybalchenko V, Ahuja M, Coblentz J, Churamani D, Patel S. 77.  et al. 2012. Membrane potential regulates nicotinic acid adenine dinucleotide phosphate (NAADP) dependence of the pH- and Ca2+-sensitive organellar two-pore channel TPC1. J. Biol. Chem. 287:20407–16 [Google Scholar]
  78. Jha A, Ahuja M, Patel S, Brailoiu E, Muallem S. 78.  2014. Convergent regulation of the lysosomal two-pore channel-2 by Mg2+, NAADP, PI(3,5)P2 and multiple protein kinases. EMBO J. 33:501–11 [Google Scholar]
  79. Cheng X, Shen D, Samie M, Xu H. 79.  2010. Mucolipins: intracellular TRPML1–3 channels. FEBS Lett. 584:2013–21 [Google Scholar]
  80. Bargal R, Avidan N, Olender T. Asher E, Zeigler M. 80. , Ben et al. 2001. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum. Mutat. 17:397–402 [Google Scholar]
  81. Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC. 81.  et al. 2000. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum. Mol. Genet. 9:2471–78 [Google Scholar]
  82. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M. 82.  et al. 2009. A gene network regulating lysosomal biogenesis and function. Science 325:473–77 [Google Scholar]
  83. Grimm C, Hassan S, Wahl-Schott C, Biel M. 83.  2012. Role of TRPML and two-pore channels in endolysosomal cation homeostasis. J. Pharmacol. Exp. Ther. 342:236–44 [Google Scholar]
  84. Vergarajauregui S, Puertollano R. 84.  2006. Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes. Traffic 7:337–53 [Google Scholar]
  85. Pryor PR, Reimann F, Gribble FM, Luzio JP. 85.  2006. Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic. Traffic 7:1388–98 [Google Scholar]
  86. Abe K, Puertollano R. 86.  2011. Role of TRP channels in the regulation of the endosomal pathway. Physiology 26:14–22 [Google Scholar]
  87. Zhang X, Li X, Xu H. 87.  2012. Phosphoinositide isoforms determine compartment-specific ion channel activity. Proc. Natl. Acad. Sci. USA 109:11384–89 [Google Scholar]
  88. Dong XP, Shen D, Wang X, Dawson T, Li X. 88.  et al. 2010. PI(3,5)P2 controls membrane traffic by direct activation of mucolipin Ca release channels in the endolysosome. Nat. Commun. 1:38 [Google Scholar]
  89. Di Paolo G, De Camilli P. 89.  2006. Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–57 [Google Scholar]
  90. McCartney AJ, Zhang Y, Weisman LS. 90.  2014. Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance. BioEssays 36:52–64 [Google Scholar]
  91. Falkenburger BH, Jensen JB, Dickson EJ, Suh BC, Hille B. 91.  2010. Phosphoinositides: lipid regulators of membrane proteins. J. Physiol. 588:3179–85 [Google Scholar]
  92. Li X, Wang X, Zhang X, Zhao M, Tsang WL. 92.  et al. 2013. Genetically encoded fluorescent probe to visualize intracellular phosphatidylinositol 3,5-bisphosphate localization and dynamics. Proc. Natl. Acad. Sci. USA 110:21165–70 [Google Scholar]
  93. Grimm C, Jors S, Saldanha SA, Obukhov AG, Pan B. 93.  et al. 2010. Small molecule activators of TRPML3. Chem. Biol. 17:135–48 [Google Scholar]
  94. Shen D, Wang X, Xu H. 94.  2011. Pairing phosphoinositides with calcium ions in endolysosomal dynamics: Phosphoinositides control the direction and specificity of membrane trafficking by regulating the activity of calcium channels in the endolysosomes. BioEssays 33:448–57 [Google Scholar]
  95. Thompson EG, Schaheen L, Dang H, Fares H. 95.  2007. Lysosomal trafficking functions of mucolipin-1 in murine macrophages. BMC Cell Biol. 8:54 [Google Scholar]
  96. Vergarajauregui S, Connelly PS, Daniels MP, Puertollano R. 96.  2008. Autophagic dysfunction in muco-lipidosis type IV patients. Hum. Mol. Genet. 17:2723–37 [Google Scholar]
  97. Curcio-Morelli C, Charles FA, Micsenyi MC, Cao Y, Venugopal B. 97.  et al. 2010. Macroautophagy is defective in mucolipin-1-deficient mouse neurons. Neurobiol. Dis. 40:370–77 [Google Scholar]
  98. Wong CO, Li R, Montell C, Venkatachalam K. 98.  2012. Drosophila TRPML is required for TORC1 activation. Curr. Biol. 22:1616–21 [Google Scholar]
  99. Chen CS, Bach G, Pagano RE. 99.  1998. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc. Natl. Acad. Sci. USA 95:6373–78 [Google Scholar]
  100. Treusch S, Knuth S, Slaugenhaupt SA, Goldin E, Grant BD, Fares H. 100.  2004. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc. Natl. Acad. Sci. USA 101:4483–88 [Google Scholar]
  101. Dong XP, Wang X, Shen D, Chen S, Liu M. 101.  et al. 2009. Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis. J. Biol. Chem. 284:32040–52 [Google Scholar]
  102. LaPlante JM, Sun M, Falardeau J, Dai D, Brown EM. 102.  et al. 2006. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol. Genet. Metab. 89:339–48 [Google Scholar]
  103. Aderem A, Underhill DM. 103.  1999. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17:593–623 [Google Scholar]
  104. McNeil PL, Kirchhausen T. 104.  2005. An emergency response team for membrane repair. Nat. Rev. Mol. Cell Biol. 6:499–505 [Google Scholar]
  105. Cheng X, Zhang X, Gao Q, Azar M, Tsang WL. 105.  et al. 2014. An intracellular Ca2+ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy. Nature Med. 20:1187–92 [Google Scholar]
  106. Babst M. 106.  2011. MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between. Curr. Opin. Cell Biol. 23:452–57 [Google Scholar]
  107. Arredouani A, Evans AM, Ma J, Parrington J, Zhu MX, Galione A. 107.  2010. An emerging role for NAADP-mediated Ca2+ signaling in the pancreatic β-cell. Islets 2:323–30 [Google Scholar]
  108. Ishibashi K, Suzuki M, Imai M. 108.  2000. Molecular cloning of a novel form (two-repeat) protein related to voltage-gated sodium and calcium channels. Biochem. Biophys. Res. Commun. 270:370–76 [Google Scholar]
  109. Brailoiu E, Hooper R, Cai X, Brailoiu GC, Keebler MV. 109.  et al. 2010. An ancestral deuterostome family of two-pore channels mediates nicotinic acid adenine dinucleotide phosphate–dependent calcium release from acidic organelles. J. Biol. Chem. 285:2897–901 [Google Scholar]
  110. Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A. 110.  et al. 2009. NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature 459:596–600 [Google Scholar]
  111. Cang C, Zhou Y, Navarro B, Seo Y-J, Aranda K. 111.  et al. 2013. mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152:778–90 [Google Scholar]
  112. Boccaccio A, Scholz-Starke J, Hamamoto S, Larisch N, Festa M. 112.  et al. 2014. The phosphoinositide PI(3,5)P2 mediates activation of mammalian but not plant TPC proteins: functional expression of endolysosomal channels in yeast and plant cells. Cell. Mol. Life Sci. 714275–83
  113. Bridges D, Ma JT, Park S, Inoki K, Weisman LS, Saltiel AR. 113.  2012. Phosphatidylinositol 3,5-bisphosphate plays a role in the activation and subcellular localization of mechanistic target of rapamycin 1. Mol. Biol. Cell 23:2955–62 [Google Scholar]
  114. Nichols CG. 114.  2006. KATP channels as molecular sensors of cellular metabolism. Nature 440:470–76 [Google Scholar]
  115. Laplante M, Sabatini DM. 115.  2012. mTOR signaling in growth control and disease. Cell 149:274–93 [Google Scholar]
  116. Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. 116.  2001. Mammalian TOR: a homeo-static ATP sensor. Science 294:1102–5 [Google Scholar]
  117. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 117.  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]
  118. Pitt SJ, Funnell TM, Sitsapesan M, Venturi E, Rietdorf K. 118.  et al. 2010. TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. J. Biol. Chem. 285:35039–46 [Google Scholar]
  119. Morgan AJ, Galione A. 119.  2014. Two-pore channels (TPCs): current controversies. BioEssays 36:173–83 [Google Scholar]
  120. Lin-Moshier Y, Walseth TF, Churamani D, Davidson SM, Slama JT. 120.  et al. 2012. Photoaffinity labeling of nicotinic acid adenine dinucleotide phosphate (NAADP) targets in mammalian cells. J. Biol. Chem. 287:2296–307 [Google Scholar]
  121. Ichas F, Jouaville LS, Mazat JP. 121.  1997. Mitochondria are excitable organelles capable of generating and conveying electrical and calcium signals. Cell 89:1145–53 [Google Scholar]
  122. Davis LC, Morgan AJ, Chen JL, Snead CM, Bloor-Young D. 122.  et al. 2012. NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. Curr. Biol. 22:2331–37 [Google Scholar]
  123. Notomi T, Ezura Y, Noda M. 123.  2012. Identification of two-pore channel 2 as a novel regulator of osteoclastogenesis. J. Biol. Chem. 287:35057–64 [Google Scholar]
  124. Bolton E, Bayliss R, Kalungia CA, Bloor-Young D, Ruas da Silva M. 124.  et al. 2013. The involvement of NAADP and two-pore Ca2+ channels in the cardiac β-adrenergic response Presented at Biophys. Soc. Annu. Meet., 58th, Philadelphia, Feb. 2–6
  125. Pereira GJ, Hirata H, Fimia GM, do Carmo LG, Bincoletto C. 125.  et al. 2011. Nicotinic acid adenine dinucleotide phosphate (NAADP) regulates autophagy in cultured astrocytes. J. Biol. Chem. 286:27875–81 [Google Scholar]
  126. Durlu-Kandilci NT, Ruas M, Chuang KT, Brading A, Parrington J, Galione A. 126.  2010. TPC2 proteins mediate nicotinic acid adenine dinucleotide phosphate (NAADP)- and agonist-evoked contractions of smooth muscle. J. Biol. Chem. 285:24925–32 [Google Scholar]
  127. Grimm C, Holdt LM, Chen CC, Hassan S, Muller C. 127.  et al. 2014. High susceptibility to fatty liver disease in two-pore channel 2 deficient mice. Nat. Commun. 5:4699
  128. Arndt L, Castonguay J, Arlt E, Meyer D, Hassan S. 128.  et al. 2014. NAADP and the two-pore channel protein 1 participate in the acrosome reaction in mammalian spermatozoa. Mol. Biol. Cell 25:948–64 [Google Scholar]
  129. Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T. 129.  et al. 2008. Two newly identified genetic determinants of pigmentation in Europeans. Nat. Genet. 40:835–37 [Google Scholar]
  130. Choi WG, Toyota M, Kim SH, Hilleary R, Gilroy S. 130.  2014. Salt stress–induced Ca2+ waves are associated with rapid, long-distance root-to-shoot signaling in plants. Proc. Natl. Acad. Sci. USA 111:6497–502 [Google Scholar]
  131. Bonaventure G, Gfeller A, Proebsting WM, Hortensteiner S, Chetelat A. 131.  et al. 2007. A gain-of-function allele of TPC1 activates oxylipin biogenesis after leaf wounding in Arabidopsis. Plant J. 49:889–98 [Google Scholar]
  132. Venkatachalam K, Long AA, Elsaesser R, Nikolaeva D, Broadie K, Montell C. 132.  2008. Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135:838–51 [Google Scholar]
  133. Spampanato C, Feeney E, Li L, Cardone M, Lim JA. 133.  et al. 2013. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol. Med. 5:691–706 [Google Scholar]
  134. Sardiello M, Ballabio A. 134.  2009. Lysosomal enhancement: a CLEAR answer to cellular degradative needs. Cell Cycle 8:4021–22 [Google Scholar]

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