Involvement of members of the Rab family and related small GTPases in autophagosome formation and maturation

  • Christelle En Lin Chua
  • Bin Qi Gan
  • Bor Luen Tang


Macroautophagy, the process by which cytosolic components and organelles are engulfed and degraded by a double-membrane structure, could be viewed as a specialized, multistep membrane transport process. As such, it intersects with the exocytic and endocytic membrane trafficking pathways. A number of Rab GTPases which regulate secretory and endocytic membrane traffic have been shown to play either critical or accessory roles in autophagy. The biogenesis of the pre-autophagosomal isolation membrane (or phagophore) is dependent on the functionality of Rab1. A non-canonical, Atg5/Atg7-independent mode of autophagosome generation from the trans-Golgi or endosome requires Rab9. Other Rabs, such as Rab5, Rab24, Rab33, and Rab7 have all been shown to be required, or involved at various stages of autophagosomal genesis and maturation. Another small GTPase, RalB, was very recently demonstrated to induce isolation membrane formation and maturation via its engagement of the exocyst complex, a known Rab effector. We summarize here what is now known about the involvement of Rabs in autophagy, and discuss plausible mechanisms with future perspectives.


Autophagy Autophagosome Parkinson’s disease Rab RalB 



Rab-associated work in BLT’s laboratory was supported by a grant from the Biomedical Research Council (08/1/21/19/533). SNARE-associated work was funded by an AcRF tier 1 grant from the Ministry of Education of Singapore (Project no. T13-0802-P13). CEC is a recipient of the NUS Graduate School of Integrative Sciences and Engineering (NGS) scholarship. The authors declare no financial conflicts of interest.


  1. 1.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721PubMedCrossRefGoogle Scholar
  2. 2.
    Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822PubMedCrossRefGoogle Scholar
  3. 3.
    Kroemer G, Mariño G, Levine B (2010) Autophagy and the integrated stress response. Mol cell 40:280–293PubMedCrossRefGoogle Scholar
  4. 4.
    Mariño G, Madeo F, Kroemer G (2010) Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol 23:198–206Google Scholar
  5. 5.
    Banerjee R, Beal MF, Thomas B (2010) Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 33:541–549PubMedCrossRefGoogle Scholar
  6. 6.
    Xilouri M, Stefanis L (2010) Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets 9:701–719PubMedGoogle Scholar
  7. 7.
    Beau I, Mehrpour M, Codogno P (2011) Autophagosomes and human diseases. Int J Biochem Cell Biol 43:460–464PubMedCrossRefGoogle Scholar
  8. 8.
    Mathew R, White E (2011) Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev 21:113–119PubMedCrossRefGoogle Scholar
  9. 9.
    Rosenfeldt MT, Ryan KM (2011) The multiple roles of autophagy in cancer. CarcinogenesisGoogle Scholar
  10. 10.
    Reggiori F, Klionsky DJ (2002) Autophagy in the eukaryotic cell. Eukaryotic Cell 1:11–21PubMedCrossRefGoogle Scholar
  11. 11.
    Mari M, Griffith J, Rieter E, Krishnappa L, Klionsky DJ, Reggiori F (2010) An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. J Cell Biol 190:1005–1022PubMedCrossRefGoogle Scholar
  12. 12.
    Hamasaki M, Yoshimori T (2010) Where do they come from? Insights into autophagosome formation. FEBS Lett 584:1296–1301PubMedCrossRefGoogle Scholar
  13. 13.
    Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12:831–835PubMedCrossRefGoogle Scholar
  14. 14.
    Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701PubMedCrossRefGoogle Scholar
  15. 15.
    Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A (2009) A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 11:1433–1437PubMedCrossRefGoogle Scholar
  16. 16.
    Ylä-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL (2009) 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5:1180–1185PubMedCrossRefGoogle Scholar
  17. 17.
    Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–667PubMedCrossRefGoogle Scholar
  18. 18.
    Longatti A, Tooze SA (2009) Vesicular trafficking and autophagosome formation. Cell Death Differ 16:956–965PubMedCrossRefGoogle Scholar
  19. 19.
    Noda T, Fujita N, Yoshimori T (2009) The late stages of autophagy: how does the end begin? Cell Death Differ 16:984–990PubMedCrossRefGoogle Scholar
  20. 20.
    Itakura E, Mizushima N (2010) Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6:764–776PubMedCrossRefGoogle Scholar
  21. 21.
    Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131PubMedCrossRefGoogle Scholar
  22. 22.
    Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141PubMedCrossRefGoogle Scholar
  23. 23.
    Reggiori F, Tucker KA, Stromhaug PE, Klionsky DJ (2004) The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev Cell 6:79–90PubMedCrossRefGoogle Scholar
  24. 24.
    Young ARJ, Chan EYW, Hu XW, Köchl R, Crawshaw SG, High S, Hailey DW, Lippincott-Schwartz J, Tooze SA (2006) Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 119:3888–3900PubMedCrossRefGoogle Scholar
  25. 25.
    Cheong H, Nair U, Geng J, Klionsky DJ (2008) The Atg1 kinase complex is involved in the regulation of protein recruitment to initiate sequestering vesicle formation for nonspecific autophagy in Saccharomyces cerevisiae. Mol Biol Cell 19:668–681PubMedCrossRefGoogle Scholar
  26. 26.
    Sekito T, Kawamata T, Ichikawa R, Suzuki K, Ohsumi Y (2009) Atg17 recruits Atg9 to organize the pre-autophagosomal structure. Genes Cells Devot Mol Cell Mech 14:525–538CrossRefGoogle Scholar
  27. 27.
    Simonsen A, Tooze SA (2009) Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol 186:773–782PubMedCrossRefGoogle Scholar
  28. 28.
    van der Vaart A, Griffith J, Reggiori F (2010) Exit from the Golgi is required for the expansion of the autophagosomal phagophore in yeast Saccharomyces cerevisiae. Mol Biol Cell 21:2270–2284PubMedCrossRefGoogle Scholar
  29. 29.
    Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T (2008) The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19:2092–2100PubMedCrossRefGoogle Scholar
  30. 30.
    Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T, Komatsu M, Otsu K, Tsujimoto Y, Shimizu S (2009) Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461:654–658PubMedCrossRefGoogle Scholar
  31. 31.
    Takahashi Y, Meyerkord CL, Wang HG (2009) Bif-1/endophilin B1: a candidate for crescent driving force in autophagy. Cell Death Differ 16:947–955PubMedCrossRefGoogle Scholar
  32. 32.
    Orsi A, Polson HEJ, Tooze SA (2010) Membrane trafficking events that partake in autophagy. Curr Opin Cell Biol 22:150–156PubMedCrossRefGoogle Scholar
  33. 33.
    Metcalf D, Isaacs AM (2010) The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes. Biochem Soc Trans 38:1469–1473PubMedCrossRefGoogle Scholar
  34. 34.
    Razi M, Chan EYW, Tooze SA (2009) Early endosomes and endosomal coatomer are required for autophagy. J Cell Biol 185:305–321PubMedCrossRefGoogle Scholar
  35. 35.
    Fader CM, Colombo MI (2009) Autophagy and multivesicular bodies: two closely related partners. Cell Death Differ 16:70–78PubMedCrossRefGoogle Scholar
  36. 36.
    Ishihara N, Hamasaki M, Yokota S, Suzuki K, Kamada Y, Kihara A, Yoshimori T, Noda T, Ohsumi Y (2001) Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol Biol Cell 12:3690–3702PubMedGoogle Scholar
  37. 37.
    Zoppino FCM, Militello RD, Slavin I, Alvarez C, Colombo MI (2010) Autophagosome formation depends on the small GTPase Rab1 and functional ER exit sites. Traffic 11:1246–1261PubMedCrossRefGoogle Scholar
  38. 38.
    Li L, Kim E, Yuan H, Inoki K, Goraksha-Hicks P, Schiesher RL, Neufeld TP, Guan KL (2010) Regulation of mTORC1 by the Rab and Arf GTPases. J Biol Chem 285:19705–19709PubMedCrossRefGoogle Scholar
  39. 39.
    Munafó DB, Colombo MI (2002) Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic 3:472–482PubMedCrossRefGoogle Scholar
  40. 40.
    Itoh T, Fujita N, Kanno E, Yamamoto A, Yoshimori T, Fukuda M (2008) Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. Mol Biol Cell 19:2916–2925PubMedCrossRefGoogle Scholar
  41. 41.
    Renna M, Schaffner C, Winslow AR, Menzies FM, Peden AA, Floto RA, Rubinsztein DC (2011) Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. J Cell Sci 124:469–482PubMedCrossRefGoogle Scholar
  42. 42.
    Ravikumar B, Imarisio S, Sarkar S, O’Kane CJ, Rubinsztein DC (2008) Rab5 modulates aggregation and toxicity of mutant huntingtin through macroautophagy in cell and fly models of Huntington disease. J Cell Sci 121:1649–1660PubMedCrossRefGoogle Scholar
  43. 43.
    Gutierrez MG, Munafó DB, Berón W, Colombo MI (2004) Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 117:2687–2697PubMedCrossRefGoogle Scholar
  44. 44.
    Jäger S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848PubMedCrossRefGoogle Scholar
  45. 45.
    Fader CM, Sánchez 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 1793:1901–1916PubMedCrossRefGoogle Scholar
  46. 46.
    Furuta N, Fujita N, Noda T, Yoshimori T, Amano A (2010) Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol Biol Cell 21:1001–1010PubMedCrossRefGoogle Scholar
  47. 47.
    Kwon SI, Cho HJ, Jung JH, Yoshimoto K, Shirasu K, Park OK (2010) The Rab GTPase RabG3b functions in autophagy and contributes to tracheary element differentiation in Arabidopsis. Plant J Cell Mol Biol 64:151–164Google Scholar
  48. 48.
    Plutner H, Cox AD, Pind S, Khosravi-Far R, Bourne JR, Schwaninger R, Der CJ, Balch WE (1991) Rab1b regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments. J Cell Biol 115:31–43PubMedCrossRefGoogle Scholar
  49. 49.
    De Antoni A, Schmitzová J, Trepte HH, Gallwitz D, Albert S (2002) Significance of GTP hydrolysis in Ypt1p-regulated endoplasmic reticulum to Golgi transport revealed by the analysis of two novel Ypt1-GAPs. J Biol Chem 277:41023–41031PubMedCrossRefGoogle Scholar
  50. 50.
    Lynch-Day MA, Bhandari D, Menon S, Huang J, Cai H, Bartholomew CR, Brumell JH, Ferro-Novick S, Klionsky DJ (2010) Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy. Proc Natl Acad Sci USA 107:7811–7816Google Scholar
  51. 51.
    Jones S, Newman C, Liu F, Segev N (2000) The TRAPP complex is a nucleotide exchanger for Ypt1 and Ypt31/32. Mol Biol Cell 11:4403–4411PubMedGoogle Scholar
  52. 52.
    Wang W, Sacher M, Ferro-Novick S (2000) TRAPP stimulates guanine nucleotide exchange on Ypt1p. J Cell Biol 151:289–296PubMedCrossRefGoogle Scholar
  53. 53.
    Barrowman J, Bhandari D, Reinisch K, Ferro-Novick S (2010) TRAPP complexes in membrane traffic: convergence through a common Rab. Nature reviews. Mol Cell Biol 11:759–763Google Scholar
  54. 54.
    Sacher M, Barrowman J, Wang W, Horecka J, Zhang Y, Pypaert M, Ferro-Novick S (2001) TRAPP I implicated in the specificity of tethering in ER-to-Golgi transport. Mol Cell 7:433–442PubMedCrossRefGoogle Scholar
  55. 55.
    Yamasaki A, Menon S, Yu S, Barrowman J, Meerloo T, Oorschot V, Klumperman J, Satoh A, Ferro-Novick S (2009) mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles. Mol Biol Cell 20:4205–4215PubMedCrossRefGoogle Scholar
  56. 56.
    Meiling-Wesse K, Epple UD, Krick R, Barth H, Appelles A, Voss C, Eskelinen EL, Thumm M (2005) Trs85 (Gsg1), a component of the TRAPP complexes, is required for the organization of the preautophagosomal structure during selective autophagy via the Cvt pathway. J Biol Chem 280:33669–33678PubMedCrossRefGoogle Scholar
  57. 57.
    Nazarko TY, Huang J, Nicaud JM, Klionsky DJ, Sibirny AA (2005) Trs85 is required for macroautophagy, pexophagy and cytoplasm to vacuole targeting in Yarrowia lipolytica and Saccharomyces cerevisiae. Autophagy 1:37–45PubMedCrossRefGoogle Scholar
  58. 58.
    Bannykh SI, Nishimura N, Balch WE (1998) Getting into the Golgi. Trends Cell Biol 8:21–25PubMedCrossRefGoogle Scholar
  59. 59.
    Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76PubMedCrossRefGoogle Scholar
  60. 60.
    Huang J, Birmingham CL, Shahnazari S, Shiu J, Zheng YT, Smith AC, Campellone KG, Heo WD, Gruenheid S, Meyer T, Welch MD, Ktistakis NT, Kim PK, Klionsky DJ, Brumell JH (2011) Antibacterial autophagy occurs at PI(3)P-enriched domains of the endoplasmic reticulum and requires Rab1 GTPase. Autophagy 7:17–26PubMedCrossRefGoogle Scholar
  61. 61.
    Winslow AR, Chen CW, Corrochano S, Acevedo-Arozena A, Gordon DE, Peden AA, Lichtenberg M, Menzies FM, Ravikumar B, Imarisio S, Brown S, O’Kane CJ, Rubinsztein DC (2010) α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol 190:1023–1037PubMedCrossRefGoogle Scholar
  62. 62.
    Jin M, Saucan L, Farquhar MG, Palade GE (1996) Rab1a and multiple other Rab proteins are associated with the transcytotic pathway in rat liver. J Biol Chem 271:30105–30113PubMedCrossRefGoogle Scholar
  63. 63.
    Mukhopadhyay A, Nieves E, Che FY, Wang J, Jin L, Murray JW, Gordon K, Angeletti RH, Wolkoff AW (2011) Proteomic analysis of endocytic vesicles: Rab1a regulates motility of early endocytic vesicles. J Cell Sci 124:765–775PubMedCrossRefGoogle Scholar
  64. 64.
    Barbero P, Bittova L, Pfeffer SR (2002) Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol 156:511–518PubMedCrossRefGoogle Scholar
  65. 65.
    Egami Y, Kiryu-Seo S, Yoshimori T, Kiyama H (2005) Induced expressions of Rab24 GTPase and LC3 in nerve-injured motor neurons. Biochem Biophys Res Commun 337:1206–1213PubMedCrossRefGoogle Scholar
  66. 66.
    Zheng JY, Koda T, Arimura Y, Kishi M, Kakinuma M (1997) Structure and expression of the mouse S10 gene. Biochim Biophys Acta 1351:47–50PubMedGoogle Scholar
  67. 67.
    Zheng JY, Koda T, Fujiwara T, Kishi M, Ikehara Y, Kakinuma M (1998) A novel Rab GTPase, Rab33B, is ubiquitously expressed and localized to the medial Golgi cisternae. J Cell Sci 111(Pt 8):1061–1069PubMedGoogle Scholar
  68. 68.
    Valsdottir R, Hashimoto H, Ashman K, Koda T, Storrie B, Nilsson T (2001) Identification of rabaptin-5, rabex-5, and GM130 as putative effectors of rab33b, a regulator of retrograde traffic between the Golgi apparatus and ER. FEBS Lett 508:201–209PubMedCrossRefGoogle Scholar
  69. 69.
    Starr T, Sun Y, Wilkins N, Storrie B (2010) Rab33b and Rab6 are functionally overlapping regulators of Golgi homeostasis and trafficking. Traffic 11:626–636PubMedCrossRefGoogle Scholar
  70. 70.
    Fukuda M, Itoh T (2008) Direct link between Atg protein and small GTPase Rab: Atg16L functions as a potential Rab33 effector in mammals. Autophagy 4:824–826PubMedGoogle Scholar
  71. 71.
    Fader CM, Savina A, Sánchez D, Colombo MI (2005) Exosome secretion and red cell maturation: Exploring molecular components involved in the docking and fusion of multivesicular bodies in K562 cells. Blood Cells Mol Dis 35:153–157PubMedCrossRefGoogle Scholar
  72. 72.
    Fader CM, Sánchez D, Furlán M, Colombo MI (2008) Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic 9:230–250PubMedCrossRefGoogle Scholar
  73. 73.
    Yamaguchi H, Nakagawa I, Yamamoto A, Amano A, Noda T, Yoshimori T (2009) An initial step of GAS-containing autophagosome-like vacuoles formation requires Rab7. PLoS pathogens 5:e1000670PubMedCrossRefGoogle Scholar
  74. 74.
    Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A, Bjørkøy G, Johansen T (2010) FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J Cell Biol 188:253–269PubMedCrossRefGoogle Scholar
  75. 75.
    Bodemann BO, White MA (2008) Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nature reviews. Cancer 8:133–140PubMedGoogle Scholar
  76. 76.
    Camonis JH, White MA (2005) Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol 15:327–332PubMedCrossRefGoogle Scholar
  77. 77.
    He B, Guo W (2009) The exocyst complex in polarized exocytosis. Curr Opin Cell Biol 21:537–542PubMedCrossRefGoogle Scholar
  78. 78.
    Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396PubMedCrossRefGoogle Scholar
  79. 79.
    Bodemann BO, Orvedahl A, Cheng T, Ram RR, Ou YH, Formstecher E, Maiti M, Hazelett CC, Wauson EM, Balakireva M, Camonis JH, Yeaman C, Levine B, White MA (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144:253–267PubMedCrossRefGoogle Scholar
  80. 80.
    Novick P, Guo W (2002) Ras family therapy: Rab, Rho and Ral talk to the exocyst. Trends Cell Biol 12:247–249PubMedCrossRefGoogle Scholar
  81. 81.
    Auluck PK, Caraveo G, Lindquist S (2010) α-Synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol 26:211–233PubMedCrossRefGoogle Scholar
  82. 82.
    Chua CEL, Tang BL (2011) Rabs, SNAREs and α-synuclein—membrane trafficking defects in synucleinopathies. Brain Res RevGoogle Scholar
  83. 83.
    Uversky VN (2008) Alpha-synuclein misfolding and neurodegenerative diseases. Curr Protein Pept Sci 9:507–540PubMedCrossRefGoogle Scholar
  84. 84.
    Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S (2006) Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 313:324–328PubMedCrossRefGoogle Scholar
  85. 85.
    Gitler AD, Bevis BJ, Shorter J, Strathearn KE, Hamamichi S, Su LJ, Caldwell KA, Caldwell GA, Rochet JC, McCaffery JM, Barlowe C, Lindquist S (2008) The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci USA 105:145–150Google Scholar
  86. 86.
    Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, Pentchev PG, Pavan WJ (1997) Murine model of Niemann–Pick C disease: mutation in a cholesterol homeostasis gene. Science 277:232–235PubMedCrossRefGoogle Scholar
  87. 87.
    Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P (2000) Identification of HE1 as the second gene of Niemann–Pick C disease. Science 290:2298–2301PubMedCrossRefGoogle Scholar
  88. 88.
    Ko DC, Milenkovic L, Beier SM, Manuel H, Buchanan J, Scott MP (2005) Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann–Pick type C disease. PLoS Genet 1:81–95PubMedCrossRefGoogle Scholar
  89. 89.
    Narita K, Choudhury A, Dobrenis K, Sharma DK, Holicky EL, Marks DL, Walkley SU, Pagano RE (2005) Protein transduction of Rab9 in Niemann–Pick C cells reduces cholesterol storage. FASEB J Off Publ Fed Am Soc Exp Biol 19:1558–1560Google Scholar
  90. 90.
    Linder MD, Uronen RL, Hölttä-Vuori M, van der Sluijs P, Peränen J, Ikonen E (2007) Rab8-dependent recycling promotes endosomal cholesterol removal in normal and sphingolipidosis cells. Mol Biol Cell 18:47–56PubMedCrossRefGoogle Scholar
  91. 91.
    Kaptzan T, West SA, Holicky EL, Wheatley CL, Marks DL, Wang T, Peake KB, Vance J, Walkley SU, Pagano RE (2009) Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of Niemann–Pick type C disease. Am J Pathol 174:14–20PubMedCrossRefGoogle Scholar
  92. 92.
    Oxford G, Owens CR, Titus BJ, Foreman TL, Herlevsen MC, Smith SC, Theodorescu D (2005) RalA and RalB: antagonistic relatives in cancer cell migration. Cancer Res 65:7111–7120PubMedCrossRefGoogle Scholar
  93. 93.
    Maehama T, Tanaka M, Nishina H, Murakami M, Kanaho Y, Hanada K (2008) RalA functions as an indispensable signal mediator for the nutrient-sensing system. J Biol Chem 283:35053–35059PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Christelle En Lin Chua
    • 1
  • Bin Qi Gan
    • 1
  • Bor Luen Tang
    • 1
  1. 1.Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health SystemNational University of SingaporeSingaporeSingapore

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