Skip to main content
SpringerLink
Log in

Exosomes in the Preservation of Cellular Homeostasis

  • Chapter
  • First Online:
Inflammation, Aging, and Oxidative Stress

  • 1295 Accesses

Abstract

Cells are exposed to a variety of stress conditions during their lifetime. Accumulation of intracellular damage results in loss of protein homeostasis (proteostasis) and cell function, and underlies many pathophysiological disorders and contributes to aging. To limit cellular damage, dedicated quality‐ control mechanisms maintain a healthy proteome by detecting altered proteins and assisting in their refolding, sequestration in specific subcellular compartments, or elimination. The main catabolic mechanisms involved are the ubiquitin‐proteasome and the lysosome‐autophagy pathways, which mediate specific degradation of damaged proteins and organelles and the recycling of the degraded components. In addition, damaged or stress‐inducing intracellular components (e.g., altered proteins, RNA or DNA) can be eliminated from cells by secretion in small vesicles known as exosomes. Clearance of damaged material through exosomes might contribute to the systemic propagation of protective or detrimental signaling responses throughout the organism, adding a new layer of complexity to the pathophysiological consequences of failed cellular quality control. Here, we discuss the evidence that selective incorporation and release of cellular compounds in exosomes is a quality‐control strategy to alleviate intracellular stress. We describe how exosome biogenesis and the autophagy‐lysosomal pathway converge at the endolysosomal compartment for the proper maintenance of intracellular homeostasis. Finally, we highlight how dysregulation of these processes contributes to human disease and aging.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem. 2009;78:959–91.

    Article  CAS  PubMed  Google Scholar 

  2. Taylor RC, Berendzen KM, Dillin A. Systemic stress signalling: understanding the cell non‐autonomous control of proteostasis. Nat Rev Mol Cell Biol. 2014;15:211–7.

    Article  CAS  PubMed  Google Scholar 

  3. McClellan AJ, Tam S, Kaganovich D, Frydman J. Protein quality control: chaperones culling corrupt conformations. Nat Cell Biol. 2005;7:736–41.

    Article  CAS  PubMed  Google Scholar 

  4. Bagola K, Sommer T. Protein quality control: on IPODs and other JUNQ. Curr Biol. 2008;18:R1019–21.

    Article  CAS  PubMed  Google Scholar 

  5. Kaganovich D, Kopito R, Frydman J. Misfolded proteins partition between two distinct quality control compartments. Nature. 2008;454:1088–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baixauli F, Lopez‐Otin C, Mittelbrunn M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 2014;5:403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bellingham SA, Guo BB, Coleman BM, Hill AF. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol. 2012;3:124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen B, Retzlaff M, Roos T, Frydman J. Cellular strategies of protein quality control. Cold Spring Harb Perspect Biol. 2011;3:a004374.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tyedmers J, Mogk A, Bukau B. Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol. 2010;11:777–88.

    Article  CAS  PubMed  Google Scholar 

  10. Vilchez D, Saez I, Dillin A. The role of protein clearance mechanisms in organismal ageing and age‐related diseases. Nat Commun. 2014;5:5659.

    Article  CAS  PubMed  Google Scholar 

  11. Wolff S, Weissman JS, Dillin A. Differential scales of protein quality control. Cell. 2014;157:52–64.

    Article  CAS  PubMed  Google Scholar 

  12. Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nat Rev Mol Cell Biol. 2007;8:622–32.

    Article  CAS  PubMed  Google Scholar 

  13. Rink J, Ghigo E, Kalaidzidis Y, Zerial M. Rab conversion as a mechanism of progression from early to late endosomes. Cell. 2005;122:735–49.

    Article  CAS  PubMed  Google Scholar 

  14. Hanson PI, Cashikar A. Multivesicular body morphogenesis. Annu Rev Cell Dev Biol. 2012;28:337–62.

    Article  CAS  PubMed  Google Scholar 

  15. Mittelbrunn M, Sanchez‐Madrid F. Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol. 2012;13:328–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol. 2009;10:623–35.

    Article  CAS  PubMed  Google Scholar 

  17. Lamb CA, Dooley HC, Tooze SA. Endocytosis and autophagy: shared machinery for degradation. Bioessays. 2013;35:34–45.

    Article  CAS  PubMed  Google Scholar 

  18. Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14:759–74.

    Article  CAS  PubMed  Google Scholar 

  19. Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold‐transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol. 1984;35:256–63.

    CAS  PubMed  Google Scholar 

  20. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262:9412–20.

    CAS  PubMed  Google Scholar 

  21. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nolte‐’t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, t Hoen PA. Deep sequencing of RNA from immune cell‐derived vesicles uncovers the selective incorporation of small non‐coding RNA biotypes with potential regulatory functions. Nucleic Acids Res. 2012;40:9272–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Villarroya‐Beltri C, Baixauli F, Gutierrez‐Vazquez C, Sanchez‐Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. 2014. Semin Cancer Biol.

    Google Scholar 

  24. Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Mobius W, Goebbels S, Nave KA, et al. Neurotransmitter‐triggered transfer of exosomes mediates oligodendrocyte‐neuron communication. PLoS Biol. 2013;11, e1001604.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Gutierrez‐Vazquez C, Villarroya‐Beltri C, Mittelbrunn M, Sanchez‐Madrid F. Transfer of extracellular vesicles during immune cell‐cell interactions. Immunol Rev. 2013;251:125–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Mittelbrunn M, Gutierrez‐Vazquez C, Villarroya‐Beltri C, Gonzalez S, Sanchez‐Cabo F, Gonzalez MA, Bernad A, Sanchez‐Madrid F. Unidirectional transfer of microRNA‐loaded exosomes from T cells to antigen‐presenting cells. Nat Commun. 2011;2:282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa‐Silva B, Moreno‐Bueno G, Hergueta‐Redondo M, Williams C, Garcia‐Santos G, Ghajar C, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro‐metastatic phenotype through MET. Nat Med. 2012;18:883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14:195–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.

    Article  CAS  PubMed  Google Scholar 

  30. Edgar JR, Eden ER, Futter CE. Hrs‐ and CD63‐dependent competing mechanisms make different sized endosomal intraluminal vesicles. Traffic. 2014;15:197–211.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell. 2011;21:77–91.

    Article  CAS  PubMed  Google Scholar 

  32. Bilodeau PS, Winistorfer SC, Kearney WR, Robertson AD, Piper RC. Vps27‐Hse1 and ESCRT‐I complexes cooperate to increase efficiency of sorting ubiquitinated proteins at the endosome. J Cell Biol. 2003;163:237–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Katzmann DJ, Stefan CJ, Babst M, Emr SD. Vps27 recruits ESCRT machinery to endosomes during MVB sorting. J Cell Biol. 2003;162:413–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, et al. Syndecan‐syntenin‐ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012;14:677–85.

    Article  CAS  PubMed  Google Scholar 

  35. Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, Manel N, Moita LF, Thery C, Raposo G. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci. 2013;126:5553–65.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu H, Guariglia S, Yu RY, Li W, Brancho D, Peinado H, Lyden D, Salzer J, Bennett C, Chow CW. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Bioi Cell. 2013;24(1619–1637):S1611–3.

    Google Scholar 

  37. Putz U, Howitt J, Doan A, Goh CP, Low LH, Silke J, Tan SS. The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci Signal. 2012;5:70.

    Article  CAS  Google Scholar 

  38. Stuffers S, Sem Wegner C, Stenmark H, Brech A. Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic. 2009;10:925–37.

    Article  CAS  PubMed  Google Scholar 

  39. van Niel G, Charrin S, Simoes S, Romao M, Rochin L, Saftig P, Marks MS, Rubinstein E, Raposo G. The tetraspanin CD63 regulates ESCRT‐independent and ‐dependent endosomal sorting during melanogenesis. Dev Cell. 2011;21:708–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Perez‐Hernandez D, Gutierrez‐Vazquez C, Jorge I, Lopez‐Martin S, Ursa A, Sanchez‐Madrid F, Vazquez J, Yanez‐Mo M. The intracellular interactome of tetraspanin‐enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem. 2013;288:11649–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–7.

    Article  CAS  PubMed  Google Scholar 

  42. Ghossoub R, Lembo F, Rubio A, Gaillard CB, Bouchet J, Vitale N, Slavik J, Machala M, Zimmermann P. Syntenin‐ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun. 2014;5:3477.

    Article  PubMed  CAS  Google Scholar 

  43. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L. Microautophagy of cytosolic proteins by late endosomes. Dev Cell. 2011;20:131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Geminard C, De Gassart A, Blanc L, Vidal M. Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TFR for sorting into exosomes. Traffic. 2004;5:181–93.

    Article  CAS  PubMed  Google Scholar 

  45. Moreno‐Gonzalo O, Villarroya‐Beltri C, Sanchez‐Madrid F. Post‐translational modifications of exosomal proteins. Front Immunol. 2014;5:383.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Burke MC, Oei MS, Edwards NJ, Ostrand‐Rosenberg S, Fenselau C. Ubiquitinated proteins in exosomes secreted by myeloid‐derived suppressor cells. J Proteome Res. 2014;13:5965–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee HS, Jeong J, Lee KJ. Characterization of vesicles secreted from insulinoma NIT‐1 cells. J Proteome Res. 2009;8:2851–62.

    Article  CAS  PubMed  Google Scholar 

  48. Zuccato E, Blatt EJ, Holt O, Sigismund S, Shaw M, Bossi G, Griffiths GM. Sorting of Fas ligand to secretory lysosomes is regulated by mono-ubiquitylation and phosphorylation. J Cell Sci. 2007;120:191–9.

    Article  CAS  PubMed  Google Scholar 

  49. Valapala M, Vishwanatha JK. Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2. J Biol Chem. 2011;286:30911–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, et al. Exosome‐associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9.

    Article  CAS  PubMed  Google Scholar 

  51. Surgucheva I, Sharov VS, Surguchov A. gamma‐Synuclein: seeding of alpha‐synuclein aggregation and transmission between cells. Biochemistry. 2012;51:4743–54.

    Article  CAS  PubMed  Google Scholar 

  52. Villarroya‐Beltri C, Gutierrez‐Vazquez C, Sanchez‐Cabo F, Perez‐Hernandez D, Vazquez J, Martin‐Cofreces N, Martinez‐Herrera DJ, Pascual‐Montano A, Mittelbrunn M, Sanchez‐Madrid F. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Koppers‐Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MA, Sadek P, Sie D, Zini N, Middeldorp JM, Ylstra B, de Menezes RX, et al. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 2014;8:1649–58.

    Article  PubMed  CAS  Google Scholar 

  54. Saunderson SC, Schuberth PC, Dunn AC, Miller L, Hock BD, MacKay PA, Koch N, Jack RW, McLellan AD. Induction of exosome release in primary B cells stimulated via CD40 and the IL‐4 receptor. J Immunol. 2008;180:8146–52.

    Article  CAS  PubMed  Google Scholar 

  55. Yeh YY, Ozer HG, Lehman AM, Maddocks K, Yu L, Johnson AJ, Byrd JC. Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of B‐cell receptor signaling. 2015. Blood.

    Google Scholar 

  56. Qu Y, Franchi L, Nunez G, Dubyak GR. Nonclassical IL‐1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J Immunol. 2007;179:1913–25.

    Article  CAS  PubMed  Google Scholar 

  57. Savina A, Furlan M, Vidal M, Colombo MI. Exosome release is regulated by a calcium‐dependent mechanism in K562 cells. J Biol Chem. 2003;278:20083–90.

    Article  CAS  PubMed  Google Scholar 

  58. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32:623–42.

    Article  CAS  PubMed  Google Scholar 

  59. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL. Hypoxia‐inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2014;111:E3234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR‐135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor‐inhibiting HIF‐1. Blood. 2014;124:3748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284:34211–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hedlund M, Nagaeva O, Kargl D, Baranov V, Mincheva‐Nilsson L. Thermal‐ and oxidative stress causes enhanced release of NKG2D ligand‐bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells. PLoS One. 2011;6, e16899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Amzallag N, Passer BJ, Allanic D, Segura E, Thery C, Goud B, Amson R, Telerman A. TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine‐releasing factor via a nonclassical pathway. J Biol Chem. 2004;279:46104–12.

    Article  CAS  PubMed  Google Scholar 

  65. Feng Y, Huang W, Wani M, Yu X, Ashraf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR‐22. PLoS One. 2014;9, e88685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Giricz Z, Varga ZV, Baranyai T, Sipos P, Paloczi K, Kittel A, Buzas EI, Ferdinandy P. Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol. 2014;68:75–8.

    Article  CAS  PubMed  Google Scholar 

  67. Takeuchi T, Suzuki M, Fujikake N, Popiel HA, Kikuchi H, Futaki S, Wada K, Nagai Y. Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. 2015. Proceedings of the National Academy of Sciences of the United States of America.

    Google Scholar 

  68. Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14:283–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lubke T, Lobel P, Sleat DE. Proteomics of the lysosome. Biochim Biophys Acta. 2009;1793:625–35.

    Article  PubMed  CAS  Google Scholar 

  70. Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8:917–29.

    Article  CAS  PubMed  Google Scholar 

  71. Mindell JA. Lysosomal acidification mechanisms. Annu Rev Physiol. 2012;74:69–86.

    Article  CAS  PubMed  Google Scholar 

  72. Graves AR, Curran PK, Smith CL, Mindell JA. The Cl‐/H+ antiporter ClC‐7 is the primary chloride permeation pathway in lysosomes. Nature. 2008;453:788–92.

    Article  CAS  PubMed  Google Scholar 

  73. Wartosch L, Fuhrmann JC, Schweizer M, Stauber T, Jentsch TJ. Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC‐7. FASEB J. 2009;23:4056–68.

    Article  CAS  PubMed  Google Scholar 

  74. Wartosch L, Stauber T. A role for chloride transport in lysosomal protein degradation. Autophagy. 2010;6:158–9.

    Article  PubMed  Google Scholar 

  75. Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, et al. NAADP mobilizes calcium from acidic organelles through two‐pore channels. Nature. 2009;459:596–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kim HJ, Soyombo AA, Tjon‐Kon‐Sang S, So I, Muallem S. The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic. 2009;10:1157–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Soyombo AA, Tjon‐Kon‐Sang S, Rbaibi Y, Bashllari E, Bisceglia J, Muallem S, Kiselyov K. TRP‐ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J Biol Chem. 2006;281:7294–301.

    Article  CAS  PubMed  Google Scholar 

  78. Wang X, Zhang X, Dong XP, Samie M, Li X, Cheng X, Goschka A, Shen D, Zhou Y, Harlow J, et al. TPC proteins are phosphoinositide‐ activated sodium‐selective ion channels in endosomes and lysosomes. Cell. 2012;151:372–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Braulke T, Bonifacino JS. Sorting of lysosomal proteins. Biochim Biophys Acta. 2009;1793:605–14.

    Article  CAS  PubMed  Google Scholar 

  80. Coutinho MF, Prata MJ, Alves S. A shortcut to the lysosome: the mannose‐6‐phosphate‐independent pathway. Mol Genet Metab. 2012;107:257–66.

    Article  CAS  PubMed  Google Scholar 

  81. Canuel M, Korkidakis A, Konnyu K, Morales CR. Sortilin mediates the lysosomal targeting of cathepsins D and H. Biochem Biophys Res Commun. 2008;373:292–7.

    Article  CAS  PubMed  Google Scholar 

  82. Lefrancois S, Zeng J, Hassan AJ, Canuel M, Morales CR. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. EMBO J. 2003;22:6430–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ni X, Morales CR. The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6‐phosphate receptor. Traffic. 2006;7:889–902.

    Article  CAS  PubMed  Google Scholar 

  84. Zhao Y, Ren J, Padilla‐Parra S, Fry EE, Stuart DI. Lysosome sorting of beta‐glucocerebrosidase by LIMP‐2 is targeted by the mannose 6‐phosphate receptor. Nat Commun. 2014;5:4321.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325:473–7.

    CAS  PubMed  Google Scholar 

  86. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, et al. TFEB controls cellular lipid metabolism through a starvation‐induced autoregulatory loop. Nat Cell Biol. 2013;15:647–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sancak Y, Bar‐Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator‐Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141:290–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Roczniak‐Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012;5:42.

    Article  CAS  Google Scholar 

  90. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, et al. A lysosome‐to‐nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31:1095–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, Montefusco S, Scotto‐Rosato A, Prezioso C, Forrester A, et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol. 2015;17:288–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Cuervo AM, Wong E. Chaperone‐mediated autophagy: roles in disease and aging. Cell Res. 2014;24:92–104.

    Article  CAS  PubMed  Google Scholar 

  93. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self‐ digestion. Nature. 2008;451:1069–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Itakura E, Kishi‐Itakura C, Mizushima N. The hairpin‐type tail‐anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell. 2012;151:1256–69.

    Article  CAS  PubMed  Google Scholar 

  96. Takats S, Nagy P, Varga A, Pircs K, Karpati M, Varga K, Kovacs AL, Hegedus K, Juhasz G. Autophagosomal Syntaxin17‐dependent lysosomal degradation maintains neuronal function in Drosophila. J Cell Biol. 2013;201:531–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science. 1996;273:501–3.

    Article  CAS  PubMed  Google Scholar 

  98. Dice JF, Terlecky SR, Chiang HL, Olson TS, Isenman LD, Short‐Russell SR, Freundlieb S, Terlecky LJ. A selective pathway for degradation of cytosolic proteins by lysosomes. Semin Cell Biol. 1990;1:449–55.

    CAS  PubMed  Google Scholar 

  99. Chiang HL, Terlecky SR, Plant CP, Dice JF. A role for a 70‐kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science. 1989;246:382–5.

    Article  CAS  PubMed  Google Scholar 

  100. Kiffin R, Christian C, Knecht E, Cuervo AM. Activation of chaperone‐mediated autophagy during oxidative stress. Mol Biol Cell. 2004;15:4829–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Massey A, Kiffin R, Cuervo AM. Pathophysiology of chaperone‐mediated autophagy. Int J Biochem Cell Biol. 2004;36:2420–34.

    Article  CAS  PubMed  Google Scholar 

  102. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D. Impaired degradation of mutant alpha‐synuclein by chaperone‐mediated autophagy. Science. 2004;305:1292–5.

    Article  CAS  PubMed  Google Scholar 

  103. Martinez‐Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, et al. Dopamine‐modified alpha‐synuclein blocks chaperone‐mediated autophagy. J Clin Invest. 2008;118:777–88.

    PubMed  PubMed Central  Google Scholar 

  104. Koga H, Martinez‐Vicente M, Arias E, Kaushik S, Sulzer D, Cuervo AM. Constitutive upregulation of chaperone‐mediated autophagy in Huntington’s disease. J Neurosci. 2011;31:18492–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: revisiting a 40‐year‐old conundrum. Autophagy. 2011;7:673–82.

    Article  CAS  PubMed  Google Scholar 

  106. Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Klionsky DJ, Cregg JM, Dunn Jr WA, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, et al. A unified nomenclature for yeast autophagy‐related genes. Dev Cell. 2003;5:539–45.

    Article  CAS  PubMed  Google Scholar 

  108. Ohsumi Y, Mizushima N. Two ubiquitin‐like conjugation systems essential for autophagy. Semin Cell Dev Biol. 2004;15:231–6.

    Article  CAS  PubMed  Google Scholar 

  109. Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3‐kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell. 2008;19:5360–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.

    Article  CAS  PubMed  Google Scholar 

  111. Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase‐inactivated ULK proteins inhibit autophagy via their conserved C‐terminal domains using an Atg13‐independent mechanism. Mol Cell Biol. 2009;29:157–71.

    Article  CAS  PubMed  Google Scholar 

  112. Romanov J, Walczak M, Ibiricu I, Schuchner S, Ogris E, Kraft C, Martens S. Mechanism and functions of membrane binding by the Atg5‐Atg12/Atg16 complex during autophagosome formation. EMBO J. 2012;31:4304–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19:2092–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3‐phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008;182:685–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis NT, Izumi T, Noda T, Yoshimori T. Autophagy requires endoplasmic reticulum targeting of the PI3‐kinase complex via Atg14L. J Cell Biol. 2010;190:511–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hailey DW, Rambold AS, Satpute‐Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott‐Schwartz J. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141:656–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, et al. Autophagosomes form at ER‐mitochondria contact sites. Nature. 2013;495:389–93.

    Article  CAS  PubMed  Google Scholar 

  118. Ge L, Melville D, Zhang M, Schekman R. The ER‐Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. Elife. 2013;2, e00947.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Ge L, Schekman R. The ER‐Golgi intermediate compartment feeds the phagophore membrane. Autophagy. 2014;10:170–2.

    Article  CAS  PubMed  Google Scholar 

  120. Ge L, Zhang M, Schekman R. Phosphatidylinositol 3‐kinase and COPII generate LC3 lipidation vesicles from the ER‐Golgi intermediate compartment. Elife. 2014;3, e04135.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre‐autophagosomal structures. Nat Cell Biol. 2010;12:747–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F. An Atg9‐containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol. 2010;190:1005–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Moreau K, Ravikumar B, Renna M, Puri C, Rubinsztein DC. Autophagosome precursor maturation requires homotypic fusion. Cell. 2011;146:303–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Orsi A, Razi M, Dooley HC, Robinson D, Weston AE, Collinson LM, Tooze SA. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell. 2012;23:1860–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yamamoto H, Kakuta S, Watanabe TM, Kitamura A, Sekito T, Kondo‐Kakuta C, Ichikawa R, Kinjo M, Ohsumi Y. Atg9 vesicles are an important membrane source during early steps of autophagosome formation. J Cell Biol. 2012;198:219–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG, High S, Hailey DW, Lippincott‐Schwartz J, Tooze SA. Starvation and ULK1‐dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci. 2006;119:3888–900.

    Article  CAS  PubMed  Google Scholar 

  127. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki‐Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441:885–9.

    Article  CAS  PubMed  Google Scholar 

  128. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880–4.

    Article  CAS  PubMed  Google Scholar 

  129. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12:823–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Galluzzi L, Kepp O, Trojel‐Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death. Circ Res. 2012;111:1198–207.

    Article  CAS  PubMed  Google Scholar 

  132. Tsukamoto S, Kuma A, Murakami M, Kishi C, Yamamoto A, Mizushima N. Autophagy is essential for preimplantation development of mouse embryos. Science. 2008;321:117–20.

    Article  CAS  PubMed  Google Scholar 

  133. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y. Tor‐mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol. 2000;150:1507–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273:3963–6.

    Article  CAS  PubMed  Google Scholar 

  135. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL. ULK1 induces autophagy by phosphorylating Beclin‐1 and activating VPS34 lipid kinase. Nat Cell Biol. 2013;15:741–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kim J, Kim YC, Fang C, Russell RC, Kim JH, Fan W, Liu R, Zhong Q, Guan KL. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell. 2013;152:290–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Svenning S, Johansen T. Selective autophagy. Essays Biochem. 2013;55:79–92.

    Article  CAS  PubMed  Google Scholar 

  138. Birgisdottir AB, Lamark T, Johansen T. The LIR motif—crucial for selective autophagy. J Cell Sci. 2013;126:3237–47.

    CAS  PubMed  Google Scholar 

  139. Kirkin V, Lamark T, Johansen T, Dikic I. NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets. Autophagy. 2009;5:732–3.

    Article  CAS  PubMed  Google Scholar 

  140. Lamark T, Kirkin V, Dikic I, Johansen T. NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell Cycle. 2009;8:1986–90.

    Article  CAS  PubMed  Google Scholar 

  141. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science. 2011;333:228–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447:859–63.

    Article  CAS  PubMed  Google Scholar 

  143. Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP. Disease‐causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6‐dependent mitophagy. J Cell Biol. 2010;189:671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Jeong H, Then F, Melia Jr TJ, Mazzulli JR, Cui L, Savas JN, Voisine C, Paganetti P, Tanese N, Hart AC, et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell. 2009;137:60–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kim I, Rodriguez‐Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462:245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015;24:2528–38.

    Article  CAS  PubMed  Google Scholar 

  147. Zhang J, Loyd MR, Randall MS, Waddell MB, Kriwacki RW, Ney PA. A short linear motif in BNIP3L (NIX) mediates mitochondrial clearance in reticulocytes. Autophagy. 2012;8:1325–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Pallanck L, Greenamyre JT. Neurodegenerative disease: pink, parkin and the brain. Nature. 2006;441:1058.

    Article  CAS  PubMed  Google Scholar 

  149. Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183:795–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Okatsu K, Oka T, Iguchi M, Imamura K, Kosako H, Tani N, Kimura M, Go E, Koyano F, Funayama M, et al. PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria. Nat Commun. 2012;3:1016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12:9–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ponpuak M, Davis AS, Roberts EA, Delgado MA, Dinkins C, Zhao Z, Virgin HWT, Kyei GB, Johansen T, Vergne I, et al. Delivery of cytosolic components by autophagic adaptor protein p62 endows autophagosomes with unique antimicrobial properties. Immunity. 2010;32:329–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Szatmari Z, Kis V, Lippai M, Hegedus K, Farago T, Lorincz P, Tanaka T, Juhasz G, Sass M. Rab11 facilitates cross‐talk between autophagy and endosomal pathway through regulation of Hook localization. Mol Biol Cell. 2014;25:522–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Gu F, Aniento F, Parton RG, Gruenberg J. Functional dissection of COP‐I subunits in the biogenesis of multivesicular endosomes. J Cell Biol. 1997;139:1183–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Razi M, Chan EY, Tooze SA. Early endosomes and endosomal coatomer are required for autophagy. J Cell Biol. 2009;185:305–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci. 2004;117:4837–48.

    Article  PubMed  CAS  Google Scholar 

  157. Gutierrez MG, Munafo DB, Beron W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117:2687–97.

    Article  CAS  PubMed  Google Scholar 

  158. Chen Y, Zhou F, Zou S, Yu S, Li S, Li D, Song J, Li H, He Z, Hu B, et al. A Vps21 endocytic module regulates autophagy. Mol Biol Cell. 2014;25:3166–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, Vergne I, Deretic V, Feng P, Akazawa C, et al. Beclin1‐binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol. 2008;10:776–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama‐Noda K, Ichimura T, Isobe T, et al. Two Beclin 1‐binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009;11:385–96.

    Article  CAS  PubMed  Google Scholar 

  161. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1‐phosphatidylinositol‐3‐kinase complex. Nat Cell Biol. 2009;11:468–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Kim YM, Jung CH, Seo M, Kim EK, Park JM, Bae SS, Kim DH. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell. 2015;57:207–18.

    Article  CAS  PubMed  Google Scholar 

  163. Filimonenko M, Stuffers S, Raiborg C, Yamamoto A, Malerod L, Fisher EM, Isaacs A, Brech A, Stenmark H, Simonsen A. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol. 2007;179:485–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lee JA, Beigneux A, Ahmad ST, Young SG, Gao FB. ESCRT‐III dysfunction causes autophagosome accumulation and neurodegeneration. Curr Biol. 2007;17:1561–7.

    Article  CAS  PubMed  Google Scholar 

  165. Rusten TE, Stenmark H. How do ESCRT proteins control autophagy? J Cell Sci. 2009;122:2179–83.

    Article  CAS  PubMed  Google Scholar 

  166. Urwin H, Authier A, Nielsen JE, Metcalf D, Powell C, Froud K, Malcolm DS, Holm I, Johannsen P, Brown J, et al. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet. 2010;19:2228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Fader CM, Sanchez D, Furlan M, Colombo MI. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic. 2008;9:230–50.

    Article  CAS  PubMed  Google Scholar 

  168. Murrow L, Malhotra R, Debnath J. ATG12‐ATG3 interacts with Alix to promote basal autophagic flux and late endosome function. Nat Cell Biol. 2015;17:300–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ward WF. Protein degradation in the aging organism. Prog Mol Subcell Biol. 2002;29:35–42.

    Article  CAS  PubMed  Google Scholar 

  170. Lopez‐Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell. 2011;146:682–95.

    Article  CAS  PubMed  Google Scholar 

  172. Levine B, Klionsky DJ. Development by self‐digestion: molecular mechanisms and biological functions of autophagy. Dev Cell. 2004;6:463–77.

    Article  CAS  PubMed  Google Scholar 

  173. Terman A, Gustafsson B, Brunk UT. Autophagy, organelles and ageing. J Pathol. 2007;211:134–43.

    Article  CAS  PubMed  Google Scholar 

  174. Nixon RA, Mathews PM, Cataldo AM. The neuronal endosomal‐lysosomal system in Alzheimer’s disease. J Alzheimers Dis. 2001;3:97–107.

    CAS  PubMed  Google Scholar 

  175. Cuervo AM, Dice JF. Age‐related decline in chaperone‐mediated autophagy. J Biol Chem. 2000;275:31505–13.

    Article  CAS  PubMed  Google Scholar 

  176. Zhang C, Cuervo AM. Restoration of chaperone‐mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med. 2008;14:959–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Smith JA, Leonardi T, Huang B, Iraci N, Vega B, Pluchino S. Extracellular vesicles and their synthetic analogues in aging and age‐associated brain diseases. Biogerontology. 2015;16:147–85.

    Article  CAS  PubMed  Google Scholar 

  178. Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH. Autophagy, exosomes and drusen formation in age‐related macular degeneration. Autophagy. 2009;5:563–4.

    Article  CAS  PubMed  Google Scholar 

  179. Lehmann BD, Paine MS, Brooks AM, McCubrey JA, Renegar RH, Wang R, Terrian DM. Senescence‐associated exosome release from human prostate cancer cells. Cancer Res. 2008;68:7864–71.

    Article  CAS  PubMed  Google Scholar 

  180. Yu X, Riley T, Levine AJ. The regulation of the endosomal compartment by p53 the tumor suppressor gene. FEBS J. 2009;276:2201–12.

    Article  CAS  PubMed  Google Scholar 

  181. Mitsuhashi M, Taub DD, Kapogiannis D, Eitan E, Zukley L, Mattson MP, Ferrucci L, Schwartz JB, Goetzl EJ. Aging enhances release of exosomal cytokine mRNAs by Abeta1‐42‐stimulated macrophages. FASEB J. 2013;27:5141–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Dhahbi JM, Spindler SR, Atamna H, Yamakawa A, Boffelli D, Mote P, Martin DI. 5’ tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics. 2013;14:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. van Balkom BW, de Jong OG, Smits M, Brummelman J, den Ouden K, de Bree PM, van Eijndhoven MA, Pegtel DM, Stoorvogel W, Wurdinger T, et al. Endothelial cells require miR‐214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood. 2013;121(3997–4006):S3991–3915.

    Google Scholar 

  184. Pusic AD, Kraig RP. Youth and environmental enrichment generate serum exosomes containing miR‐219 that promote CNS myelination. Glia. 2014;62:284–99.

    Article  PubMed  Google Scholar 

  185. Yuyama K, Sun H, Sakai S, Mitsutake S, Okada M, Tahara H, Furukawa J, Fujitani N, Shinohara Y, Igarashi Y. Decreased amyloid‐beta pathologies by intracerebral loading of glycosphingolipid‐enriched exosomes in Alzheimer model mice. J Biol Chem. 2014;289:24488–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Perrett RM, Alexopoulou Z, Tofaris GK. The endosomal pathway in Parkinson’s disease. Mol Cell Neurosci. 2015;69:21–8.

    Article  CAS  Google Scholar 

  187. Tofaris GK. Lysosome‐dependent pathways as a unifying theme in Parkinson's disease. Movement Disord. 2012;27:1364–9.

    Article  CAS  PubMed  Google Scholar 

  188. Ginsberg SD, Mufson EJ, Counts SE, Wuu J, Alldred MJ, Nixon RA, Che S. Regional selectivity of rab5 and rab7 protein upregulation in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2010;22:631–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Schulze H, Sandhoff K. Lysosomal lipid storage diseases. Cold Spring Harb Perspect Biol. 2011;3.

    Google Scholar 

  190. Eden ER, White IJ, Tsapara A, Futter CE. Membrane contacts between endosomes and ER provide sites for PTP1B‐epidermal growth factor receptor interaction. Nat Cell Biol. 2010;12:267–72.

    CAS  PubMed  Google Scholar 

  191. Toulmay A, Prinz WA. Lipid transfer and signaling at organelle contact sites: the tip of the iceberg. Curr. Opin Cell Biol. 2011;23:458–63.

    Article  CAS  Google Scholar 

  192. Chen FW, Li C, Ioannou YA. Cyclodextrin induces calcium‐dependent lysosomal exocytosis. PLoS One. 2010;5, e15054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Strauss K, Goebel C, Runz H, Mobius W, Weiss S, Feussner I, Simons M, Schneider A. Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann‐Pick type C disease. J Biol Chem. 2010;285:26279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Klein D, Bussow H, Fewou SN, Gieselmann V. Exocytosis of storage material in a lysosomal disorder. Biochem Biophys Res Commun. 2005;327:663–7.

    Article  CAS  PubMed  Google Scholar 

  195. Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D. Deficiency of ATP13A2 leads to lysosomal dysfunction, alpha‐synuclein accumulation, and neurotoxicity. J Neurosci. 2012;32:4240–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Kong SM, Chan BK, Park JS, Hill KJ, Aitken JB, Cottle L, Farghaian H, Cole AR, Lay PA, Sue CM, et al. Parkinson’s disease‐linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes alpha‐Synuclein externalization via exosomes. Hum Mol Genet. 2014;23:2816–33.

    Article  CAS  PubMed  Google Scholar 

  197. Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and alpha‐synuclein. J Neurosci. 2014;34:15281–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Dehay B, Martinez‐Vicente M, Caldwell GA, Caldwell KA, Yue Z, Cookson MR, Klein C, Vila M, Bezard E. Lysosomal impairment in Parkinson’s disease. Movement Disord. 2013;28:725–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kalani A, Tyagi A, Tyagi N. Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol. 2014;49:590–600.

    Article  CAS  PubMed  Google Scholar 

  200. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. Alzheimer’s disease beta‐amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006;103:11172–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Grey M, Dunning CJ, Gaspar R, Grey C, Brundin P, Sparr E, Linse S. Acceleration of alpha‐synuclein aggregation by exosomes. J Biol Chem. 2015;290:2969–82.

    Article  CAS  PubMed  Google Scholar 

  202. Dinkins MB, Dasgupta S, Wang G, Zhu G, Bieberich E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging. 2014;35:1792–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Basso M, Pozzi S, Tortarolo M, Fiordaliso F, Bisighini C, Pasetto L, Spaltro G, Lidonnici D, Gensano F, Battaglia E, et al. Mutant copper‐zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J Biol Chem. 2013;288:15699–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gomes C, Keller S, Altevogt P, Costa J. Evidence for secretion of Cu, Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis. Neurosci Lett. 2007;428:43–6.

    Article  CAS  PubMed  Google Scholar 

  205. Grad LI, Yerbury JJ, Turner BJ, Guest WC, Pokrishevsky E, O’Neill MA, Yanai A, Silverman JM, Zeineddine R, Corcoran L, et al. Intercellular propagated misfolding of wild‐type Cu/Zn superoxide dismutase occurs via exosome‐dependent and ‐independent mechanisms. Proc Natl Acad Sci U S A. 2014;111:3620–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy‐deficient mice. Cell. 2007;131:1149–63.

    Article  CAS  PubMed  Google Scholar 

  208. Guo JL, Lee VM. Cell‐to‐cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med. 2014;20:130–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Danzer KM, Kranich LR, Ruf WP, Cagsal‐Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ. Exosomal cell‐to‐cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012;7:42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6:304–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F. Sanchez‐Madrid for his continuous support and advice and S. Bartlett for English editing. F.B. is supported by ERC‐2011‐AdG 294340‐GENTRIS and COST‐Action BN1202. This work is supported by the research grant CP14/0019 (Fondo de Investigación Sanitaria del Instituto de Salud Carlos III), and co-funding by Fondo Europeo de Desarrollo Regional (FEDER). The Centro Nacional de Investigaciones Cardiovasculares (CNIC, Spain) is supported by the Spanish Ministry of Science and Innovation and the Pro‐CNIC Foundation.

Author information

Authors and Affiliations

  1. Signaling and Inflammation Program, Spanish National Center for Cardiovascular Research Carlos III, Madrid, 28029, Spain

    Francesc Baixauli

  2. Immunology, La Princesa Health Research Institute, Madrid, 28006, Spain

    Francesc Baixauli

  3. Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, 28041, Spain

    Maria Mittelbrunn

Authors
  1. Francesc Baixauli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Mittelbrunn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesc Baixauli .

Editor information

Editors and Affiliations

  1. Department of Medicine, Center for Occupational and Environmental Health, University of California, Irvine, California, USA

    Stephen C. Bondy

  2. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA

    Arezoo Campbell

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Baixauli, F., Mittelbrunn, M. (2016). Exosomes in the Preservation of Cellular Homeostasis. In: Bondy, S., Campbell, A. (eds) Inflammation, Aging, and Oxidative Stress. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-33486-8_2

Download citation

Publish with us

Policies and ethics

Search

Navigation