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Rab18: new insights into the function of an essential protein

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Abstract

Rab18 is one of the small number of conserved Rab proteins which have been traced to the last eukaryotic common ancestor. It is found in organisms ranging from humans to trypanosomes, and localizes to multiple organelles, including most notably endoplasmic reticulum and lipid droplets. In humans, absence of Rab18 leads to a severe illness known as Warburg-Micro syndrome. Despite this evidence that Rab18 is essential, its role in cells remains mysterious. However, recent studies identifying effectors and interactors of Rab18, are now shedding light on its mechanism of action, suggesting functions related to organelle tethering and to autophagy. In this review, we examine the variety of roles proposed for Rab18 with a focus on new evidence giving insights into the molecular mechanisms it utilizes. Based on this summary of our current understanding, we identify priority areas for further research.

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References

  1. Chavrier P, Parton RG, Hauri H-P, Simons K, Zerial M (1990) Localization of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell 62:317–329

    Article  CAS  PubMed  Google Scholar 

  2. Yu H, Leaf DS, Moore HPH (1993) Gene cloning and characterization of a GTP-binding Rab protein from mouse pituitary AtT-20 cells. Gene 132:273–278

    Article  CAS  PubMed  Google Scholar 

  3. Lutcke A, Parton RG, Murphy C, Olkkonen VM, Dupree P, Valencia A, Simons K, Zerial M (1994) Cloning and subcellular localization of novel rab proteins reveals polarized and cell type-specific expression. J Cell Sci 107:3437–3448

    PubMed  Google Scholar 

  4. Jeffries TR, Morgan GW, Field MC (2002) TbRAB18, a developmentally regulated Golgi GTPase from Trypanosoma brucei. Mol Biochem Parasitol 121:63–74

    Article  CAS  PubMed  Google Scholar 

  5. Dejgaard SY et al (2008) Rab18 and Rab43 have key roles in ER-Golgi trafficking. J Cell Sci 121:2768–2781

    Article  CAS  PubMed  Google Scholar 

  6. Martin S, Driessen K, Nixon SJ, Zerial M, Parton RG (2005) Regulated localization of Rab18 to lipid droplets. J Biol Chem 280:42325–42335

    Article  CAS  PubMed  Google Scholar 

  7. Martin S, Parton RG (2008) Characterization of Rab18, a lipid droplet-associated small GTPase. Methods Enzymol 438:109–129

    Article  CAS  PubMed  Google Scholar 

  8. Ozeki S, Cheng J, Tauchi-Sato K, Hatano N, Taniguchi H, Fujimoto T (2005) Rab18 localizes to lipid droplets and induces their close apposition to the endoplasmic reticulum-derived membrane. J Cell Sci 118:2601–2611

    Article  CAS  PubMed  Google Scholar 

  9. Vazquez-Martinez R, Cruz-Garcia D, Duran-Prado M, Peinado JR, Castano JP, Malagon MM (2007) Rab18 inhibits secretory activity in neuroendocrine cells by interacting with secretory granules. Traffic 8:867–882

    Article  CAS  PubMed  Google Scholar 

  10. Feldmann A, Bekbulat F, Huesmann H, Ulbrich S, Tatzelt J, Behl C, Kern A (2017) The RAB GTPase RAB18 modulates macroautophagy and proteostasis. Biochim Biophys Res Comm 486:738–743

    Article  CAS  Google Scholar 

  11. Salloum S, Wang H, Ferguson C, Parton RG, Tai AW (2013) Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets. PLoS Pathog 9:e1003513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Warburg M, Sjo O, Fledelius HC, Pedersen SA (1993) Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism: micro syndrome. Am J Dis Child 147:1309–1312

    Article  CAS  PubMed  Google Scholar 

  13. Handley MT, Carpanini SM, Mali GR, Sidjanin DJ, Aligianis IA, Jackson IJ, FitzPatrick DR (2015) Warburg Micro syndrome is caused by Rab18 deficiency or dysregulation. Open Biol. 5:150047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zerial M, McBride H (2001) Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2:107–117

    Article  CAS  PubMed  Google Scholar 

  15. Bourne HR, Sanders DA, McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348:125–132

    Article  CAS  PubMed  Google Scholar 

  16. Deneka M, Neeft M, van der Sluijs P (2003) Regulation of membrane transport by rab GTPases. Crit Rev Biochem Mol Biol 38:121–142

    Article  CAS  PubMed  Google Scholar 

  17. Kabcenell AK, Goud B, Northup JK, Novick PJ (1990) Binding and hydrolysis of guanine nucleotides by Sec4p, a yeast protein involved in the regulation of vesicular traffic. J Biol Chem 265:9366–9372

    CAS  PubMed  Google Scholar 

  18. Shapiro AD, Pfeiffer SR (1995) Quantitative analysis of the interactions between prenyl Rab9, GTP dissociation inhibitor-alpha, and guanine nucleotides. J Biol Chem 270:11085–11090

    Article  CAS  PubMed  Google Scholar 

  19. Pereira-Leal JB, Hume AN, Seabra MC (2001) Prenylation of Rab GTPases: molecular mechanisms and involvement in genetic disease. FEBS Lett 498:197–200

    Article  CAS  PubMed  Google Scholar 

  20. Ullrich O, Stenmark H, Alexandrov K, Huber LA, Kaibuchi K, Sasaki T, Takai Y, Zerial M (1993) Rab GDP dissociation inhibitor as a general regulator for the membrane association of rab proteins. J Biol Chem 268:18143–18150

    CAS  PubMed  Google Scholar 

  21. Soldati T, Riederer MA, Pfeffer SR (1993) Rab GDI: a solubilizing and recycling factor for rab9 protein. Mol Biol Cell 4:425–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ishida M, Oguchi ME, Fukuda M (2016) Multiple types of guanine nucleotide exchange factors (GEFs) for Rab small GTPases. Cell Struct Funct 41:61–79

    Article  CAS  PubMed  Google Scholar 

  23. Frasa MAM, Koessmeier KT, Ahmadian MR, Braga VMM (2012) Illuminating the functional and structural repertoire of human TBC/RABGAPs. Nat Rev Mol Cell Biol 13:67–73

    Article  CAS  PubMed  Google Scholar 

  24. Fukui K, Sasaki T, Imazumi K, Matsuura Y, Nakanishi H, Takai Y (1997) Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins. J Biol Chem 272:4655–4658

    Article  CAS  PubMed  Google Scholar 

  25. Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA (2014) Rab18 and a Rab18 GEF complex are required for normal ER structure. J Cell Biol 205:707–720

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bem D et al (2011) Loss-of-function mutations in Rab18 cause Warburg micro syndrome. Am J Hum Genet 88:499–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blumer J, Rey J, Dehmelt L, Mazel T, Wu YW, Bastiaens P, Goody RS, Itzen A (2013) RabGEFs are a major determinant for specific Rab membrane targeting. J Cell Biol 200:287–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martsolf JT, Hunter AG, Haworth JC (1978) Severe mental retardation, cataracts, short stature, and primary hypogonadism in two brothers. Am J Med Genet 1:291–299

    Article  CAS  PubMed  Google Scholar 

  29. Aligianis I et al (2005) Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Nat Genet 37:221–223

    Article  CAS  PubMed  Google Scholar 

  30. Borck G et al (2011) A homozygous RAB3GAP2 mutation causes Warburg Micro syndrome. Hum Genet 129:45–50

    Article  PubMed  Google Scholar 

  31. Aligianis I et al (2006) Mutation in Rab3 GTPase-activating protein (RAB3GAP) noncatalytic subunit in a kindred with Martsolf syndrome. Am J Hum Genet 78:702–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu Q, Sun X, Yue W, Lu T, Ruan Y, Chen T, Zhang D (2016) Rab18, a protein associated with Warburg Micro syndrome controls neuronal migration in the developing cerebral cortex. Mol Brain 9:19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kawauchi T et al (2010) Rab GTPases-dependent endocytic pathways regulate neuronal migration and maturation through N-cadherin trafficking. Neuron 67:588–602

    Article  CAS  PubMed  Google Scholar 

  34. Kadowaki M, Nakamura S, Machon O, Krauss S, Radice GL, Takeichi M (2007) N-cadherin mediates cortical organization in the mouse brain. Dev Biol 304:22–33

    Article  CAS  PubMed  Google Scholar 

  35. Carpanini SM et al (2014) A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton. Dis Model Mech 7:711–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu D et al (2018) Rab18 promotes lipid droplet (LD) growth by tethering the ER to LDs through SNARE and NRZ interactions. J Cell Biol 217:975–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morishita H, Mizushima N (2016) Autophagy in the lens. Exp Eye Res 144:22–28

    Article  CAS  PubMed  Google Scholar 

  38. Morishita H, Eguchi S, Kimura H, Sasaki J, Sakamaki Y, Robinson ML, Sasaki T, Mizushima N (2013) Deletion of autophagy-related 5 (Atg5) and Pik3c3 genes in the lens causes cataract independent of programmed organelle degradation. J Biol Chem 288:11436–11447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Spang N et al (2014) RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-mediated autophagy. Autophagy 10:2297–2309

    Article  CAS  PubMed  Google Scholar 

  40. Cazares VA, Subramani A, Saldate JJ, Hoerauf W, Stuenkel EL (2014) Distinct actions of Rab3 and Rab27 GTPases on late stages of exocytosis of insulin. Traffic 15:997–1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Clabecq A, Henry JP, Darchen F (2000) Biochemical characterization of Rab3-GTPase-activating protein reveals a mechanism similar to that of Ras-GAP. J Biol Chem 275:31786–31791

    Article  CAS  PubMed  Google Scholar 

  42. Zirin J, Niewuwenhuis J, Samsonova A, Tao R, Perrimon N (2015) Regulators of autophagosome formation in Drosophila muscles. PLoS Genet 11:e1005006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Blanc-Mathieu R et al (2014) An improved genome of the model marine alga Ostreococcus tauri unfolds by assessing Illumina de novo assemblies. BMC Genom 15:1103

    Article  CAS  Google Scholar 

  44. Klopper TH, Kienle N, Fasshauer D, Munro S (2012) Untangling the evolution of Rab G proteins: implications of a comprehensive genomic analysis. BMC Biol 10:1741

    Article  CAS  Google Scholar 

  45. Gillingham AK, Sinka R, Torres IL, Lilley KS, Munro S (2014) Toward a comprehensive map of the effectors of rab GTPases. Dev Cell 31:358–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pereira MG, Visbal G, Costa TFR, Frases S, de Souza W, Atella G, Cunha-E-Silva N (2018) Trypanosoma cruzi epimastigotes store cholesteryl esters in lipid droplets after cholesterol endocytosis Mol. Biochem Parasitol 224:6–16

    Article  CAS  Google Scholar 

  47. Haines DS et al (2012) Protein interaction profiling of the p97 adaptor UBXD1 points to a role for the complex in modulating ERGIC-53 trafficking. Mol Cell Prot 11:M111–M016444

    Article  CAS  Google Scholar 

  48. Saraste J, Svensson K (1991) Distribution of the intermediate elements operating in ER to Golgi transport. J Cell Sci 100:415–430

    CAS  PubMed  Google Scholar 

  49. Appenzeller C, Andersson H, Kappeler F, Hauri H-P (1999) The lectin ERGIC-53 is a cargo transport receptor for glycoproteins. Nat Cell Biol 1:330–334

    Article  CAS  PubMed  Google Scholar 

  50. Li C, Luo X, Zhao S, Siu GKY, Liang Y, Chan HC, Satoh A, Yu SSB (2017) COPI-TRAPPII activates Rab18 and regulates its lipid droplet association. EMBO J 36:441–457

    Article  CAS  PubMed  Google Scholar 

  51. Liegel RP et al (2013) Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and warburg micro syndrome in humans. Am J Hum Genet 93:1001–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sidjanin DJ, Park AK, Ronchetti A, Martins J, Jackson WT (2016) TBC1D20 mediates autophagy as a key regulator of autophagosome maturation. Autophagy 12:1759–1775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sklan EH, Serrano RL, Einav S, Pfeffer SR, Lambright DG, Glenn JS (2007) TBC1D20 is a Rab1 GTPase-activating protein that mediates hepatitis C virus replication. J Biol Chem 282:36354–36361

    Article  CAS  PubMed  Google Scholar 

  54. Haas AK, Yoshimura S, Stephens DJ, Preisisinger C, Fuchs E, Baar FA (2007) Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells. J Cell Sci 120:2997–3010

    Article  CAS  PubMed  Google Scholar 

  55. Jacob A, Jing J, Lee J, Schedin P, Gilbert SM, Peden AA, Junutula JR, Prekeris R (2013) Rab40b regulates trafficking of MMP2 and MMP9 during invadopodia formation and invasion of breast cancer cells. J Cell Sci 126:4647–4658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tan R et al (2013) Small GTPase Rab40c associates with lipid droplets and modulates the biogenesis of lipid droplets. PLoS One 8:e63213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lui X, Li C, Tan R, Xu X, Wu KKW, Satoh A, Wang T, Yu S (2007) A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40c. Oncotarget 8:85415–85427

    Google Scholar 

  58. Wilfling F et al (2013) Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell 24:384–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wilfling F et al (2014) Arf1/COPI machinery acts directly on lipid droplets and enables their connection to the ER for protein targeting. eLIFE 3:e01607

    Article  PubMed  PubMed Central  Google Scholar 

  60. Jayson CBK, Arlt H, Fischer AW, Lai ZW, Farese RV, Walther TC (2018) Rab18 is not necessary for lipid droplet biogenesis or turnover in human mammary carcinoma cells. Mol Biol Cell 29:2045–2054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Giannakopoulou A (2017) Neuronal vacuolation and spinocerebellar degeneration associated with altered neurotransmission. Folia Neuropath 55:132–145

    Article  Google Scholar 

  62. Zhao L, Imperiale MJ (2017) Identification of Rab18 as an essential host factor for BK polyomavirus infection using a whole-genome RNA interference screen. mSphere 2:e00291-17

    Article  PubMed  PubMed Central  Google Scholar 

  63. Tang WC, Lin RJ, Liao CL, Lin YL (2014) Rab18 facilitates dengue virus infection by targeting fatty acid synthase to sites of viral replication. J Virol 88:6793–6804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. You X, Liu F, Zhang T, Li Y, Ye L, Zhang X (2013) Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells. Carciogenesis 34:1644–1652

    Article  CAS  Google Scholar 

  65. Chan SC, Lo SY, Liou JW, Lin MC, Syu CL, Lai MJ, Chen YC, Li HC (2011) Visualization of the structure of the hepatitis C virus replication complex. Biochem Biophys Res Commun 404:574–578

    Article  CAS  PubMed  Google Scholar 

  66. Dansako H, Hiramoto H, Ikeda M, Wakita T, Kato N (2014) Rab18 is required for viral assembly of hepatitis C virus through trafficking of the core protein to lipid droplets. Virology 462–463:166–174

    Article  CAS  PubMed  Google Scholar 

  67. Lavie M, Dubuisson J (2017) Interplay between hepatitis C virus and lipid metabolism during virus entry and assembly. Biochimie 141:62–69

    Article  CAS  PubMed  Google Scholar 

  68. Nelson CDS et al (2013) A retrograde trafficking inhibitor of ricin and shiga-like toxins inhibits infection of cells by human and monkey polyomaviruses. MBio. 4:e00729–e00729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sandvig K, Skotland T, van Deurs B, Klokk TI (2013) Retrograde transport of protein toxins through the Golgi apparatus. Histochem Cell Biol 140:317–326

    Article  CAS  PubMed  Google Scholar 

  70. Jakobsson A, Westerberg R, Jacobsson A (2006) Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res 45:237–249

    Article  CAS  PubMed  Google Scholar 

  71. Kistler C (2012) Functional characterisation of Rab18. Doctoral Dissertation, University of Queensland

  72. Hsu NY et al (2010) Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. Cell 141:799–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pulido MR et al (2011) Rab18 dynamics in adipocytes in relation to lipogenesis, lipolysis and obesity. PLoS One 6:e22931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL (2011) Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab 13:655–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Smirnova E, Goldberg EB, Makarova KS, Lin L, Brown WJ, Jackson CL (2006) ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. EMBO Rep 7:106–113

    Article  CAS  PubMed  Google Scholar 

  76. Clifford GM, Londos C, Kraemer FB, Vernon RG, Yeaman SJ (2000) Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes. J Biol Chem 275:5011–5015

    Article  CAS  PubMed  Google Scholar 

  77. Wang S, Soni KG, Semache M, Casavant S, Fortier M, Pan L, Mitchell GA (2008) Lipolysis and the integrated physiology of lipid energy metabolism. Mol Genet Metab 95:117–126

    Article  CAS  PubMed  Google Scholar 

  78. Fujimoto T, Parton RG (2011) Not just fat: the structure and function of the lipid droplet. Cold Spring Harb Prespect Biol 3:1–17

    Google Scholar 

  79. Ashford TP, Porter KR (1962) Cytoplasmic components in hepatic cell lysosomes. J Cell Biol 12:198–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  CAS  PubMed  Google Scholar 

  81. Singh R et al (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zechner R, Madeo F, Kratky D (2017) Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat Rev Mol Cell Biol 18:671–684

    Article  CAS  PubMed  Google Scholar 

  83. Makino A et al (2016) Acute accumulation of free cholesterol induces the degradation of perilipin 2 and Rab18-dependent fusion of ER and lipid droplets in cultured human hepatocytes. Mol Biol Cell 27:3293–3304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Behrends C, Sowa ME, Sygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466:68–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Assmann EM, Alborghetti MR, Camargo MER, Kobarg J (2006) FEZ1 dimerization and interaction with transcription regulatory proteins involves its coiled-coil region``. J Biol Chem 281:9869–9881

    Article  CAS  PubMed  Google Scholar 

  86. Kuma A, Komatsu M, Mizushima N (2017) Autophagy-monitoring and autophagy-deficient mice. Autophagy 13:1619–1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lemus L, Ribas JL, Sikorska N, Goder V (2016) An ER-localized SNARE protein is exported in specific COPII vesicles for autophagosome biogenesis. Cell Rep. 14:1710–1722

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Medical Biology, Near East University, Nicosia, Cyprus

    Selma Yilmaz Dejgaard

  2. Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, QC, H3A 0C7, Canada

    Selma Yilmaz Dejgaard & John F. Presley

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  1. Selma Yilmaz Dejgaard
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Dejgaard, S.Y., Presley, J.F. Rab18: new insights into the function of an essential protein. Cell. Mol. Life Sci. 76, 1935–1945 (2019). https://doi.org/10.1007/s00018-019-03050-3

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