The Lysosome and Intracellular Signalling

  • Geoffrey G. Hesketh
  • Lena Wartosch
  • Luther J. Davis
  • Nicholas A. Bright
  • J. Paul LuzioEmail author
Part of the Progress in Molecular and Subcellular Biology book series (PMSB, volume 57)


In addition to being the terminal degradative compartment of the cell’s endocytic and autophagic pathways, the lysosome is a multifunctional signalling hub integrating the cell’s response to nutrient status and growth factor/hormone signalling. The cytosolic surface of the limiting membrane of the lysosome is the site of activation of the multiprotein complex mammalian target of rapamycin complex 1 (mTORC1), which phosphorylates numerous cell growth-related substrates, including transcription factor EB (TFEB). Under conditions in which mTORC1 is inhibited including starvation, TFEB becomes dephosphorylated and translocates to the nucleus where it functions as a master regulator of lysosome biogenesis. The signalling role of lysosomes is not limited to this pathway. They act as an intracellular Ca2+ store, which can release Ca2+ into the cytosol for both local effects on membrane fusion and pleiotropic effects within the cell. The relationship and crosstalk between the lysosomal and endoplasmic reticulum (ER) Ca2+ stores play a role in shaping intracellular Ca2+ signalling. Lysosomes also perform other signalling functions, which are discussed. Current views of the lysosomal compartment recognize its dynamic nature. It includes endolysosomes, autolysosome and storage lysosomes that are constantly engaged in fusion/fission events and lysosome regeneration. How signalling is affected by individual lysosomal organelles being at different stages of these processes and/or at different sites within the cell is poorly understood, but is discussed.



GGH is supported by a Basic Research Fellowship from Parkinson Canada. Recent experimental work from JPL and NAB referred to in this chapter is supported by UK MRC research grant MR/M010007/1. LJD is supported by a BBSRC industrial CASE studentship with GSK Research and Development Ltd. The Cambridge Institute for Medical Research is supported by Wellcome Trust Strategic Award 100140.


  1. Allison R, Edgar JR, Pearson G, Rizo T, Newton T, Gunther S, Berner F, Hague J, Connell JW, Winkler J, Lippincott-Schwartz J, Beetz C, Winner B, Reid E (2017) Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia. J Cell Biol 216(5):1337–1355. Scholar
  2. Alonso V, Friedman PA (2013) Minireview: ubiquitination-regulated G protein-coupled receptor signaling and trafficking. Mol Endocrinol 27(4):558–572. me.2012-1404 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  3. Antonioli M, Di Rienzo M, Piacentini M, Fimia GM (2016) Emerging mechanisms in initiating and terminating autophagy. Trends Biochem Sci. Scholar
  4. 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(6):1196–1208. Scholar
  5. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM (2013) A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340(6136):1100–1106. Scholar
  6. Bento CF, Renna M, Ghislat G, Puri C, Ashkenazi A, Vicinanza M, Menzies FM, Rubinsztein DC (2016) Mammalian autophagy: how does it work? Annu Rev Biochem 85:685–713. Scholar
  7. Bowman SL, Shiwarski DJ, Puthenveedu MA (2016) Distinct G protein-coupled receptor recycling pathways allow spatial control of downstream G protein signaling. J Cell Biol 214(7):797–806. Scholar
  8. Bright NA, Reaves BJ, Mullock BM, Luzio JP (1997) Dense core lysosomes can fuse with late endosomes and are re-formed from the resultant hybrid organelles. J Cell Sci 110(Pt 17):2027–2040PubMedGoogle Scholar
  9. Bright NA, Gratian MJ, Luzio JP (2005) Endocytic delivery to lysosomes mediated by concurrent fusion and kissing events in living cells. Curr Biol 15(4):360–365. S0960982205001053 [pii]CrossRefPubMedGoogle Scholar
  10. Bright NA, Davis LJ, Luzio JP (2016) Endolysosomes are the principal intracellular sites of acid hydrolase activity. Curr Biol 26(17):2233–2245. S0960-9822(16)30687-X [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  11. Butor C, Griffiths G, Aronson NN Jr, Varki A (1995) Co-localization of hydrolytic enzymes with widely disparate pH optima: implications for the regulation of lysosomal pH. J Cell Sci 108(Pt 6):2213–2219PubMedGoogle Scholar
  12. Cao Q, Zhong XZ, Zou Y, Murrell-Lagnado R, Zhu MX, Dong XP (2015) Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion. J Cell Biol 209(6):879–894. Scholar
  13. Capel RA, Bolton EL, Lin WK, Aston D, Wang Y, Liu W, Wang X, Burton RA, Bloor-Young D, Shade KT, Ruas M, Parrington J, Churchill GC, Lei M, Galione A, Terrar DA (2015) Two-pore channels (TPC2 s) and nicotinic acid adenine dinucleotide phosphate (NAADP) at lysosomal-sarcoplasmic reticular junctions contribute to acute and chronic beta-adrenoceptor signaling in the heart. J Biol Chem 290(50):30087–30098. Scholar
  14. Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C (2016) The crucial impact of lysosomes in aging and longevity. Ageing Res Rev 32:2–12. Scholar
  15. Carnell M, Zech T, Calaminus SD, Ura S, Hagedorn M, Johnston SA, May RC, Soldati T, Machesky LM, Insall RH (2011) Actin polymerization driven by WASH causes V-ATPase retrieval and vesicle neutralization before exocytosis. J Cell Biol 193(5):831–839. Scholar
  16. Carroll B, Dunlop EA (2017) The lysosome: a crucial hub for AMPK and mTORC1 signalling. Biochem J 474(9):1453–1466. Scholar
  17. Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle RE, Mydock-McGrane L, Jiang X, van Eijkeren RJ, Davis OB, Louie SM, Perera RM, Covey DF, Nomura DK, Ory DS, Zoncu R (2017) Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science 355(6331):1306–1311. Scholar
  18. Castro-Gomes T, Corrotte M, Tam C, Andrews NW (2016) Plasma membrane repair is regulated extracellularly by proteases released from lysosomes. PLoS ONE 11(3):e0152583. Scholar
  19. Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, Wang T, Harper JW, Gygi SP, Sabatini DM (2016) The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165(1):153–164. Scholar
  20. Chou HT, Dukovski D, Chambers MG, Reinisch KM, Walz T (2016) CATCHR, HOPS and CORVET tethering complexes share a similar architecture. Nat Struct Mol Biol 23(8):761–763. nsmb.3264 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  21. Christensen KA, Myers JT, Swanson JA (2002) pH-dependent regulation of lysosomal calcium in macrophages. J Cell Sci 115(Pt 3):599–607PubMedGoogle Scholar
  22. Clapper DL, Walseth TF, Dargie PJ, Lee HC (1987) Pyridine nucleotide metabolites stimulate calcium release from sea urchin egg microsomes desensitized to inositol trisphosphate. J Biol Chem 262(20):9561–9568PubMedGoogle Scholar
  23. Colacurcio DJ, Nixon RA (2016) Disorders of lysosomal acidification-The emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev 32:75–88. Scholar
  24. Coonrod EM, Graham LA, Carpp LN, Carr TM, Stirrat L, Bowers K, Bryant NJ, Stevens TH (2013) Homotypic vacuole fusion in yeast requires organelle acidification and not the V-ATPase membrane domain. Dev Cell 27(4):462–468. Scholar
  25. de Duve C (2005) The lysosome turns fifty. Nat Cell Biol 7(9):847–849. ncb0905-847 [pii]CrossRefPubMedGoogle Scholar
  26. De Leo MG, Staiano L, Vicinanza M, Luciani A, Carissimo A, Mutarelli M, Di Campli A, Polishchuk E, Di Tullio G, Morra V, Levtchenko E, Oltrabella F, Starborg T, Santoro M, di Bernardo D, Devuyst O, Lowe M, Medina DL, Ballabio A, De Matteis MA (2016) Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nat Cell Biol 18(8):839–850. Scholar
  27. De Luca M, Cogli L, Progida C, Nisi V, Pascolutti R, Sigismund S, Di Fiore PP, Bucci C (2014) RILP regulates vacuolar ATPase through interaction with the V1G1 subunit. J Cell Sci 127(Pt 12):2697–2708. Scholar
  28. Demetriades C, Doumpas N, Teleman AA (2014) Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell 156(4):786–799. Scholar
  29. Demetriades C, Plescher M, Teleman AA (2016) Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat Commun 7:10662. Scholar
  30. Desfougeres Y, Vavassori S, Rompf M, Gerasimaite R, Mayer A (2016) Organelle acidification negatively regulates vacuole membrane fusion in vivo. Sci Rep 6:29045. Scholar
  31. Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, Zhou Q, Wilz LM, Li J, Vivona S, Pfuetzner RA, Brunger AT, Zhong Q (2015) ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature 520(7548):563–566. Scholar
  32. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47(4):535–546. Scholar
  33. Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M, Xu H (2010) PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome. Nat Commun 1:38. Scholar
  34. Dove SK, Dong K, Kobayashi T, Williams FK, Michell RH (2009) Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function. Biochem J 419(1):1–13. Scholar
  35. Du X, Kumar J, Ferguson C, Schulz TA, Ong YS, Hong W, Prinz WA, Parton RG, Brown AJ, Yang H (2011) A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking. J Cell Biol 192(1):121–135. Scholar
  36. Du W, Su QP, Chen Y, Zhu Y, Jiang D, Rong Y, Zhang S, Zhang Y, Ren H, Zhang C, Wang X, Gao N, Wang Y, Sun L, Sun Y, Yu L (2016) Kinesin 1 drives autolysosome tubulation. Dev Cell 37(4):326–336. Scholar
  37. Ebner M, Lucic I, Leonard TA, Yudushkin I (2017) PI(3,4,5)P3 engagement restricts Akt activity to cellular membranes. Mol Cell 65(3):416–431(e416).
  38. Edgar JR, Eden ER, Futter CE (2014) Hrs- and CD63-dependent competing mechanisms make different sized endosomal intraluminal vesicles. Traffic 15(2):197–211. Scholar
  39. Eltschinger S, Loewith R (2016) TOR complexes and the maintenance of cellular homeostasis. Trends Cell Biol 26(2):148–159. Scholar
  40. Fader CM, Sanchez DG, Mestre MB, Colombo MI (2009) TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta 1793(12):1901–1916. S0167-4889(09)00236-5 [pii]CrossRefPubMedGoogle Scholar
  41. Feng Y, He D, Yao Z, Klionsky DJ (2014) The machinery of macroautophagy. Cell Res 24(1):24–41. cr2013168 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  42. Folick A, Oakley HD, Yu Y, Armstrong EH, Kumari M, Sanor L, Moore DD, Ortlund EA, Zechner R, Wang MC (2015) Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347(6217):83–86.
  43. Folts CJ, Scott-Hewitt N, Proschel C, Mayer-Proschel M, Noble M (2016) Lysosomal re-acidification prevents lysosphingolipid-induced lysosomal impairment and cellular toxicity. PLoS Biol 14(12):e1002583. Scholar
  44. Fraldi A, Annunziata F, Lombardi A, Kaiser HJ, Medina DL, Spampanato C, Fedele AO, Polishchuk R, Sorrentino NC, Simons K, Ballabio A (2010) Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J 29(21):3607–3620. Scholar
  45. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334(6054):358–362. Scholar
  46. Fujiwara T, Ye S, Castro-Gomes T, Winchell CG, Andrews NW, Voth DE, Varughese KI, Mackintosh SG, Feng Y, Pavlos N, Nakamura T, Manolagas SC, Zhao H (2016) PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis. JCI Insight 1(17):e86330. Scholar
  47. Garrity AG, Wang W, Collier CM, Levey SA, Gao Q, Xu H (2016) The endoplasmic reticulum, not the pH gradient, drives calcium refilling of lysosomes. Elife 5.
  48. Gatta AT, Levine TP (2016) Piecing Together the Patchwork of Contact Sites. Trends Cell Biol. Scholar
  49. Goh LK, Sorkin A (2013) Endocytosis of receptor tyrosine kinases. Cold Spring Harb Perspect Biol 5(5):a017459. a017459, 5/5/a017459 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  50. Goldman SD, Krise JP (2010) Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo. J Biol Chem 285(7):4983–4994. Scholar
  51. Gowrishankar S, Ferguson SM (2016) Lysosomes relax in the cellular suburbs. J Cell Biol 212(6):617–619. Scholar
  52. Grimm C, Holdt LM, Chen CC, Hassan S, Muller C, Jors S, Cuny H, Kissing S, Schroder B, Butz E, Northoff B, Castonguay J, Luber CA, Moser M, Spahn S, Lullmann-Rauch R, Fendel C, Klugbauer N, Griesbeck O, Haas A, Mann M, Bracher F, Teupser D, Saftig P, Biel M, Wahl-Schott C (2014) High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nat Commun 5:4699. Scholar
  53. Guardia CM, Farias GG, Jia R, Pu J, Bonifacino JS (2016) BORC functions upstream of kinesins 1 and 3 to coordinate regional movement of lysosomes along different microtubule tracks. Cell Rep 17(8):1950–1961. Scholar
  54. Guo B, Liang Q, Li L, Hu Z, Wu F, Zhang P, Ma Y, Zhao B, Kovacs AL, Zhang Z, Feng D, Chen S, Zhang H (2014) O-GlcNAc-modification of SNAP-29 regulates autophagosome maturation. Nat Cell Biol 16(12):1215–1226. Scholar
  55. Hamalisto S, Jaattela M (2016) Lysosomes in cancer-living on the edge (of the cell). Curr Opin Cell Biol 39:69–76. Scholar
  56. Hammond GR, Takasuga S, Sasaki T, Balla T (2015) The ML1Nx2 phosphatidylinositol 3,5-bisphosphate probe shows poor selectivity in cells. PLoS ONE 10(10):e0139957. Scholar
  57. Hariri H, Ugrankar R, Liu Y, Henne WM (2016) Inter-organelle ER-endolysosomal contact sites in metabolism and disease across evolution. Commun Integr Biol 9(3):e1156278. Scholar
  58. Hickey CM, Wickner W (2010) HOPS initiates vacuole docking by tethering membranes before trans-SNARE complex assembly. Mol Biol Cell 21(13):2297–2305. E10-01-0044 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  59. Hirst J, Edgar JR, Esteves T, Darios F, Madeo M, Chang J, Roda RH, Durr A, Anheim M, Gellera C, Li J, Zuchner S, Mariotti C, Stevanin G, Blackstone C, Kruer MC, Robinson MS (2015) Loss of AP-5 results in accumulation of aberrant endolysosomes: defining a new type of lysosomal storage disease. Hum Mol Genet 24(17):4984–4996. Scholar
  60. Holland P, Torgersen ML, Sandvig K, Simonsen A (2014) LYST affects lysosome size and quantity, but not trafficking or degradation through autophagy or endocytosis. Traffic 15(12):1390–1405. Scholar
  61. Huotari J, Helenius A (2011) Endosome maturation. EMBO J 30(17):3481–3500. emboj2011286 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  62. Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590CrossRefPubMedPubMedCentralGoogle Scholar
  63. 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(6):1256–1269. S0092-8674(12)01336-0 [pii]CrossRefPubMedGoogle Scholar
  64. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, Mizushima N (2014) The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol Biol Cell 25(8):1327–1337. Scholar
  65. Jin N, Lang MJ, Weisman LS (2016) Phosphatidylinositol 3,5-bisphosphate: regulation of cellular events in space and time. Biochem Soc Trans 44(1):177–184. Scholar
  66. Johnson DE, Ostrowski P, Jaumouille V, Grinstein S (2016) The position of lysosomes within the cell determines their luminal pH. J Cell Biol 212(6):677–692. Scholar
  67. Jongsma ML, Berlin I, Wijdeven RH, Janssen L, Janssen GM, Garstka MA, Janssen H, Mensink M, van Veelen PA, Spaapen RM, Neefjes J (2016) An ER-associated pathway defines endosomal architecture for controlled cargo transport. Cell 166(1):152–166. Scholar
  68. Jordens I, Fernandez-Borja M, Marsman M, Dusseljee S, Janssen L, Calafat J, Janssen H, Wubbolts R, Neefjes J (2001) The Rab7 effector protein RILP controls lysosomal transport by inducing the recruitment of dynein-dynactin motors. Curr Biol 11(21):1680–1685CrossRefPubMedGoogle Scholar
  69. Jung J, Genau HM, Behrends C (2015) Amino acid-dependent mTORC1 regulation by the lysosomal Membrane protein SLC38A9. Mol Cell Biol 35(14):2479–2494. Scholar
  70. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11(5):373–384. Scholar
  71. Khatter D, Raina VB, Dwivedi D, Sindhwani A, Bahl S, Sharma M (2015) The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes. J Cell Sci 128(9):1746–1761. jcs.162651 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  72. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. Scholar
  73. Kim YM, Jung CH, Seo M, Kim EK, Park JM, Bae SS, Kim DH (2015) mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell 57(2):207–218. Scholar
  74. Korolchuk VI, Saiki S, Lichtenberg M, Siddiqi FH, Roberts EA, Imarisio S, Jahreiss L, Sarkar S, Futter M, Menzies FM, O’Kane CJ, Deretic V, Rubinsztein DC (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13(4):453–460. Scholar
  75. Kruppa AJ, Kendrick-Jones J, Buss F (2016) Myosins, actin and autophagy. Traffic 17(8):878–890. Scholar
  76. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. Scholar
  77. Lassen KG, McKenzie CI, Mari M, Murano T, Begun J, Baxt LA, Goel G, Villablanca EJ, Kuo SY, Huang H, Macia L, Bhan AK, Batten M, Daly MJ, Reggiori F, Mackay CR, Xavier RJ (2016) Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity 44(6):1392–1405. Scholar
  78. Li X, Wang X, Zhang X, Zhao M, Tsang WL, Zhang Y, Yau RG, Weisman LS, Xu H (2013) Genetically encoded fluorescent probe to visualize intracellular phosphatidylinositol 3,5-bisphosphate localization and dynamics. Proc Natl Acad Sci U S A 110(52):21165–21170. Scholar
  79. Li SC, Diakov TT, Xu T, Tarsio M, Zhu W, Couoh-Cardel S, Weisman LS, Kane PM (2014) The signaling lipid PI(3,5)P(2) stabilizes V(1)-V(0) sector interactions and activates the V-ATPase. Mol Biol Cell 25(8):1251–1262. Scholar
  80. Li Y, Xu M, Ding X, Yan C, Song Z, Chen L, Huang X, Wang X, Jian Y, Tang G, Tang C, Di Y, Mu S, Liu X, Liu K, Li T, Wang Y, Miao L, Guo W, Hao X, Yang C (2016) Protein kinase C controls lysosome biogenesis independently of mTORC1. Nat Cell Biol 18(10):1065–1077. Scholar
  81. Lim CY, Zoncu R (2016) The lysosome as a command-and-control center for cellular metabolism. J Cell Biol 214(6):653–664. Scholar
  82. Lin X, Yang T, Wang S, Wang Z, Yun Y, Sun L, Zhou Y, Xu X, Akazawa C, Hong W, Wang T (2014) RILP interacts with HOPS complex via VPS41 subunit to regulate endocytic trafficking. Sci Rep 4:7282. srep07282 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  83. Lloyd-Evans E, Platt FM (2011) Lysosomal Ca2+ homeostasis: role in pathogenesis of lysosomal storage diseases. Cell Calcium 50(2):200–205. Scholar
  84. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM (2008) Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14(11):1247–1255. Scholar
  85. Lopez-Sanjurjo CI, Tovey SC, Prole DL, Taylor CW (2013) Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum. J Cell Sci 126(Pt 1):289–300. Scholar
  86. Luzio JP, Pryor PR, Bright NA (2007) Lysosomes: fusion and function. Nat Rev Mol Cell Biol 8(8):622–632. nrm2217 [pii]CrossRefPubMedGoogle Scholar
  87. Luzio JP, Hackmann Y, Dieckmann NM, Griffiths GM (2014) The biogenesis of lysosomes and lysosome-related organelles. Cold Spring Harb Perspect Biol 6(9):a016840. a016840, 6/9/a016840 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  88. MacDonald C, Stamnes MA, Katzmann DJ, Piper RC (2015) Tetraspan cargo adaptors usher GPI-anchored proteins into multivesicular bodies. Cell Cycle 14(23):3673–3678. Scholar
  89. Majer O, Liu B, Barton GM (2016) Nucleic acid-sensing TLRs: trafficking and regulation. Curr Opin Immunol 44:26–33. Scholar
  90. Manifava M, Smith M, Rotondo S, Walker S, Niewczas I, Zoncu R, Clark J, Ktistakis NT (2016) Dynamics of mTORC1 activation in response to amino acids. Elife 5.
  91. Martens S, Nakamura S, Yoshimori T (2016) Phospholipids in autophagosome formation and fusion. J Mol Biol. Scholar
  92. Martina JA, Puertollano R (2013) Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol 200(4):475–491. Scholar
  93. Martina JA, Diab HI, Brady OA, Puertollano R (2016) TFEB and TFE3 are novel components of the integrated stress response. EMBO J 35(5):479–495. Scholar
  94. Marwaha R, Arya SB, Jagga D, Kaur H, Tuli A, Sharma M (2017) The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes. J Cell Biol 216(4):1051–1070. Scholar
  95. Mauvezin C, Nagy P, Juhasz G, Neufeld TP (2015) Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification. Nat Commun 6:7007. Scholar
  96. McEwan DG, Dikic I (2015) PLEKHM1: adapting to life at the lysosome. Autophagy 11(4):720–722. Scholar
  97. McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, Coxon FP, Miranda de Stegmann D, Bhogaraju S, Maddi K, Kirchof A, Gatti E, Helfrich MH, Wakatsuki S, Behrends C, Pierre P, Dikic I (2015) PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell 57(1):39–54. Scholar
  98. Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, Puri C, Pignata A, Martina JA, Sardiello M, Palmieri M, Polishchuk R, Puertollano R, Ballabio A (2011) Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell 21(3):421–430. Scholar
  99. Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, Montefusco S, Scotto-Rosato A, Prezioso C, Forrester A, Settembre C, Wang W, Gao Q, Xu H, Sandri M, Rizzuto R, De Matteis MA, Ballabio A (2015) Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol 17(3):288–299. Scholar
  100. Melchionda M, Pittman JK, Mayor R, Patel S (2016) Ca2+/H+ exchange by acidic organelles regulates cell migration in vivo. J Cell Biol 212(7):803–813. Scholar
  101. Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, Cantley LC, Manning BD (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156(4):771–785. Scholar
  102. Metcalf D, Isaacs AM (2010) The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes. Biochem Soc Trans 38(6):1469–1473. Scholar
  103. Miller A, Schafer J, Upchurch C, Spooner E, Huynh J, Hernandez S, McLaughlin B, Oden L, Fares H (2015) Mucolipidosis type IV protein TRPML1-dependent lysosome formation. Traffic 16(3):284–297. Scholar
  104. Morgan AJ, Platt FM, Lloyd-Evans E, Galione A (2011) Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem J 439(3):349–374. Scholar
  105. Napolitano G, Ballabio A (2016) TFEB at a glance. J Cell Sci 129(13):2475–2481. Scholar
  106. Nguyen TN, Padman BS, Usher J, Oorschot V, Ramm G, Lazarou M (2016) Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J Cell Biol 215(6):857–874. Scholar
  107. Nguyen ON, Grimm C, Schneider LS, Chao YK, Atzberger C, Bartel K, Watermann A, Ulrich M, Mayr D, Wahl-Schott C, Biel M, Vollmar AM (2017) Two-pore channel function is crucial for migration of invasive cancer cells. Cancer Res. Scholar
  108. Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A (2011) Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 20(19):3852–3866. Scholar
  109. Palmieri M, Pal R, Nelvagal HR, Lotfi P, Stinnett GR, Seymour ML, Chaudhury A, Bajaj L, Bondar VV, Bremner L, Saleem U, Tse DY, Sanagasetti D, Wu SM, Neilson JR, Pereira FA, Pautler RG, Rodney GG, Cooper JD, Sardiello M (2017) mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun 8:14338. Scholar
  110. Parra KJ, Kane PM (1998) Reversible association between the V1 and V0 domains of yeast vacuolar H+ -ATPase is an unconventional glucose-induced effect. Mol Cell Biol 18(12):7064–7074CrossRefPubMedPubMedCentralGoogle Scholar
  111. Peng M, Yin N, Li MO (2017) SZT2 dictates GATOR control of mTORC1 signalling. Nature. Scholar
  112. Penny CJ, Kilpatrick BS, Eden ER, Patel S (2015) Coupling acidic organelles with the ER through Ca2+ microdomains at membrane contact sites. Cell Calcium 58(4):387–396. Scholar
  113. Perera RM, Zoncu R (2016) The lysosome as a regulatory hub. Annu Rev Cell Dev Biol 32:223–253. Scholar
  114. 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(7):1107–1122. Scholar
  115. Pislar A, Perisic Nanut M, Kos J (2015) Lysosomal cysteine peptidases—molecules signaling tumor cell death and survival. Semin Cancer Biol 35:168–179. Scholar
  116. Pitt SJ, Funnell TM, Sitsapesan M, Venturi E, Rietdorf K, Ruas M, Ganesan A, Gosain R, Churchill GC, Zhu MX, Parrington J, Galione A, Sitsapesan R (2010) TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. J Biol Chem 285(45):35039–35046. Scholar
  117. Platt FM, Boland B, van der Spoel AC (2012) The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 199(5):723–734. Scholar
  118. Platta HW, Stenmark H (2011) Endocytosis and signaling. Curr Opin Cell Biol 23(4):393–403. S0955-0674(11)00025-1 [pii]CrossRefPubMedGoogle Scholar
  119. Pols MS, ten Brink C, Gosavi P, Oorschot V, Klumperman J (2013) The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion. Traffic 14(2):219–232. Scholar
  120. Pryor PR, Mullock BM, Bright NA, Gray SR, Luzio JP (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(5):1053–1062CrossRefPubMedPubMedCentralGoogle Scholar
  121. Pryor PR, Mullock BM, Bright NA, Lindsay MR, Gray SR, Richardson SC, Stewart A, James DE, Piper RC, Luzio JP (2004) Combinatorial SNARE complexes with VAMP7 or VAMP8 define different late endocytic fusion events. EMBO Rep 5(6):590–595. 7400150 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  122. Pu J, Schindler C, Jia R, Jarnik M, Backlund P, Bonifacino JS (2015) BORC, a multisubunit complex that regulates lysosome positioning. Dev Cell 33(2):176–188. Scholar
  123. Raben N, Puertollano R (2016) TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Annu Rev Cell Dev Biol 32:255–278. Scholar
  124. Raffaello A, Mammucari C, Gherardi G, Rizzuto R (2016) Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends Biochem Sci 41(12):1035–1049. Scholar
  125. Rao SK, Huynh C, Proux-Gillardeaux V, Galli T, Andrews NW (2004) Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis. J Biol Chem 279(19):20471–20479. Scholar
  126. Rebsamen M, Pochini L, Stasyk T, de Araujo ME, Galluccio M, Kandasamy RK, Snijder B, Fauster A, Rudashevskaya EL, Bruckner M, Scorzoni S, Filipek PA, Huber KV, Bigenzahn JW, Heinz LX, Kraft C, Bennett KL, Indiveri C, Huber LA, Superti-Furga G (2015) SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 519(7544):477–481. Scholar
  127. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM (2012) The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal 5(228):ra42.
  128. Ronco V, Potenza DM, Denti F, Vullo S, Gagliano G, Tognolina M, Guerra G, Pinton P, Genazzani AA, Mapelli L, Lim D, Moccia F (2015) A novel Ca2+-mediated cross-talk between endoplasmic reticulum and acidic organelles: implications for NAADP-dependent Ca2+ signalling. Cell Calcium 57(2):89–100. Scholar
  129. Rong Y, McPhee CK, Deng S, Huang L, Chen L, Liu M, Tracy K, Baehrecke EH, Yu L, Lenardo MJ (2011) Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci U S A 108(19):7826–7831. Scholar
  130. Rong Y, Liu M, Ma L, Du W, Zhang H, Tian Y, Cao Z, Li Y, Ren H, Zhang C, Li L, Chen S, Xi J, Yu L (2012) Clathrin and phosphatidylinositol-4,5-bisphosphate regulate autophagic lysosome reformation. Nat Cell Biol 14(9):924–934. Scholar
  131. Rosa-Ferreira C, Munro S (2011) Arl8 and SKIP act together to link lysosomes to kinesin-1. Dev Cell 21(6):1171–1178. Scholar
  132. Rowland AA, Chitwood PJ, Phillips MJ, Voeltz GK (2014) ER contact sites define the position and timing of endosome fission. Cell 159(5):1027–1041. Scholar
  133. Saarikangas J, Zhao H, Lappalainen P (2010) Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. Physiol Rev 90(1):259–289. Scholar
  134. Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N, Grimm C, Wahl-Schott C, Biel M, Davey RA (2015) Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science 347(6225):995–998.
  135. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501. 1157535 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  136. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A (2009) A gene network regulating lysosomal biogenesis and function. Science 325(5939):473–477. 1174447 [pii]CrossRefPubMedGoogle Scholar
  137. Sargeant TJ, Lloyd-Lewis B, Resemann HK, Ramos-Montoya A, Skepper J, Watson CJ (2014) Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization. Nat Cell Biol 16(11):1057–1068. Scholar
  138. Sbano L, Bonora M, Marchi S, Baldassari F, Medina DL, Ballabio A, Giorgi C, Pinton P (2017) TFEB-mediated increase in peripheral lysosomes regulates store-operated calcium entry. Sci Rep 7:40797. Scholar
  139. Schafer IB, Hesketh GG, Bright NA, Gray SR, Pryor PR, Evans PR, Luzio JP, Owen DJ (2012) The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation. Nat Struct Mol Biol 19(12):1300–1309. Scholar
  140. Schmid JA, Mach L, Paschke E, Glossl J (1999) Accumulation of sialic acid in endocytic compartments interferes with the formation of mature lysosomes. Impaired proteolytic processing of cathepsin B in fibroblasts of patients with lysosomal sialic acid storage disease. J Biol Chem 274(27):19063–19071CrossRefPubMedGoogle Scholar
  141. Schulze RJ, Weller SG, Schroeder B, Krueger EW, Chi S, Casey CA, McNiven MA (2013) Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J Cell Biol 203(2):315–326. Scholar
  142. Seaman MN, Ball CL, Robinson MS (1993) Targeting and mistargeting of plasma membrane adaptors in vitro. J Cell Biol 123(5):1093–1105CrossRefPubMedGoogle Scholar
  143. Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40(2):310–322. Scholar
  144. Serrano-Puebla A, Boya P (2016) Lysosomal membrane permeabilization in cell death: new evidence and implications for health and disease. Ann N Y Acad Sci 1371(1):30–44. Scholar
  145. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31(5):1095–1108. emboj201232 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  146. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, Di Bernardo D, Chan L, Irazoqui JE, Ballabio A (2013a) TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol 15(6):647–658. Scholar
  147. 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(5):283–296. Scholar
  148. Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136(4):731–745. Scholar
  149. Sorkin A, Goh LK (2008) Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 314(17):3093–3106. Scholar
  150. Spampanato C, Feeney E, Li L, Cardone M, Lim JA, Annunziata F, Zare H, Polishchuk R, Puertollano R, Parenti G, Ballabio A, Raben N (2013) Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol Med 5(5):691–706. Scholar
  151. Steger M, Tonelli F, Ito G, Davies P, Trost M, Vetter M, Wachter S, Lorentzen E, Duddy G, Wilson S, Baptista MA, Fiske BK, Fell MJ, Morrow JA, Reith AD, Alessi DR, Mann M (2016) Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 5.
  152. Steinberg BE, Huynh KK, Brodovitch A, Jabs S, Stauber T, Jentsch TJ, Grinstein S (2010) A cation counterflux supports lysosomal acidification. J Cell Biol 189(7):1171–1186. Scholar
  153. Tian X, Gala U, Zhang Y, Shang W, Nagarkar Jaiswal S, di Ronza A, Jaiswal M, Yamamoto S, Sandoval H, Duraine L, Sardiello M, Sillitoe RV, Venkatachalam K, Fan H, Bellen HJ, Tong C (2015) A voltage-gated calcium channel regulates lysosomal fusion with endosomes and autophagosomes and is required for neuronal homeostasis. PLoS Biol 13(3):e1002103. Scholar
  154. Toyofuku T, Morimoto K, Sasawatari S, Kumanogoh A (2015) Leucine-Rich repeat kinase 1 regulates autophagy through turning on TBC1D2-dependent Rab7 inactivation. Mol Cell Biol 35(17):3044–3058. Scholar
  155. Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini DM (2013) The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 52(4):495–505. Scholar
  156. van der Kant R, Fish A, Janssen L, Janssen H, Krom S, Ho N, Brummelkamp T, Carette J, Rocha N, Neefjes J (2013) Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L. J Cell Sci 126(Pt 15):3462–3474. Scholar
  157. van der Kant R, Jonker CT, Wijdeven RH, Bakker J, Janssen L, Klumperman J, Neefjes J (2015) Characterization of the mammalian CORVET and HOPS complexes and their modular restructuring for endosome specificity. J Biol Chem 290(51):30280–30290. M115.688440 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  158. Vega-Rubin-de-Celis S, Pena-Llopis S, Konda M, Brugarolas J (2017) Multistep regulation of TFEB by MTORC1. Autophagy.
  159. Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini BL, Sabatini DM (2015) Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347(6218):188–194.
  160. Wang Z, Miao G, Xue X, Guo X, Yuan C, Wang Z, Zhang G, Chen Y, Feng D, Hu J, Zhang H (2016) The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Mol Cell 63(5):781–795. Scholar
  161. Wartosch L, Gunesdogan U, Graham SC, Luzio JP (2015) Recruitment of VPS33A to HOPS by VPS16 Is required for lysosome fusion with endosomes and autophagosomes. Traffic 16(7):727–742. Scholar
  162. Wee YS, Roundy KM, Weis JJ, Weis JH (2012) Interferon-inducible transmembrane proteins of the innate immune response act as membrane organizers by influencing clathrin and v-ATPase localization and function. Innate Immun 18(6):834–845. Scholar
  163. White IJ, Bailey LM, Aghakhani MR, Moss SE, Futter CE (2006) EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation. EMBO J 25(1):1–12. Scholar
  164. Wijdeven RH, Janssen H, Nahidiazar L, Janssen L, Jalink K, Berlin I, Neefjes J (2016) Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway. Nat Commun 7:11808. Scholar
  165. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, Sabatini DM (2016) Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351(6268):43–48. Scholar
  166. Wolfson RL, Chantranupong L, Wyant GA, Gu X, Orozco JM, Shen K, Condon KJ, Petri S, Kedir J, Scaria SM, Abu-Remaileh M, Frankel WN, Sabatini DM (2017) KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature. Scholar
  167. Woodman PG, Futter CE (2008) Multivesicular bodies: co-ordinated progression to maturity. Curr Opin Cell Biol 20(4):408–414. S0955-0674(08)00072-0 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  168. Yamasaki M, Thomas JM, Churchill GC, Garnham C, Lewis AM, Cancela JM, Patel S, Galione A (2005) Role of NAADP and cADPR in the induction and maintenance of agonist-evoked Ca2+ spiking in mouse pancreatic acinar cells. Curr Biol 15(9):874–878. Scholar
  169. Yamashiro DJ, Maxfield FR (1987) Acidification of morphologically distinct endosomes in mutant and wild-type Chinese hamster ovary cells. J Cell Biol 105(6 Pt 1):2723–2733CrossRefPubMedGoogle Scholar
  170. Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465(7300):942–946. Scholar
  171. Zhang H, Hu J (2016) Shaping the Endoplasmic Reticulum into a Social Network. Trends Cell Biol 26(12):934–943. Scholar
  172. Zhang CS, Jiang B, Li M, Zhu M, Peng Y, Zhang YL, Wu YQ, Li TY, Liang Y, Lu Z, Lian G, Liu Q, Guo H, Yin Z, Ye Z, Han J, Wu JW, Yin H, Lin SY, Lin SC (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(3):526–540. Scholar
  173. 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(6056):678–683. Scholar
  174. Zoncu R, Efeyan A, Sabatini DM (2011b) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21–35. Scholar
  175. Zou J, Hu B, Arpag S, Yan Q, Hamilton A, Zeng YS, Vanoye CG, Li J (2015) Reactivation of lysosomal Ca2+ efflux rescues abnormal lysosomal storage in FIG4-deficient cells. J Neurosci 35(17):6801–6812. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Geoffrey G. Hesketh
    • 1
  • Lena Wartosch
    • 2
  • Luther J. Davis
    • 2
  • Nicholas A. Bright
    • 2
  • J. Paul Luzio
    • 2
    Email author
  1. 1.Lunenfeld-Tanenbaum Research InstituteSinai Health SystemTorontoCanada
  2. 2.Department of Clinical Biochemistry and Cambridge Institute for Medical ResearchSchool of Clinical Medicine, Wellcome Trust/MRC Building, University of Cambridge, Cambridge Biomedical CampusCambridgeUK

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