Spastin Binds to Lipid Droplets and Affects Lipid Metabolism

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Hereditary spastic paraplegia (HSP) is a genetically heterogeneous neurological disease characterized by weakness and spasticity of the lower limbs, caused by progressive retrograde degeneration of the corticospinal axons, the longest in the central nervous system. The most commonly mutated gene in autosomal dominant forms of HSP, SPAST, encodes for spastin, a microtubule-severing protein. Spastin has been implicated in several processes involving remodeling of membrane structures. We now show that the longest spastin form, spastin-M1, harbors a lipid droplet targeting sequence, which allows targeting of the protein to the surface of lipid droplets, the organelles where cells store neutral lipids. Furthermore, we demonstrate that depletion of the homologous spastin proteins in both flies and worms affects lipid droplet number and triacylglycerol content. Our study adds to recent discoveries that implicate other HSP proteins in lipid droplet and lipid metabolism, and strongly suggests that lipid droplet dysfunction in neurons should be investigated to understand pathogenesis of HSP.

Vyšlo v časopise: Spastin Binds to Lipid Droplets and Affects Lipid Metabolism. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005149
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005149

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1. Fujimoto T, Parton RG. Not just fat: the structure and function of the lipid droplet. Cold Spring Harb Perspect Biol. 2011;3(3): a004838. doi: 10.1101/cshperspect.a004838 21421923

2. Walther TC, Farese RV Jr. Lipid droplets and cellular lipid metabolism. Annu Rev Biochem. 2012;81 : 687–714. doi: 10.1146/annurev-biochem-061009-102430 22524315

3. Pol A, Gross SP, Parton RG. Review: biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites. J Cell Biol. 2014;204(5):635–46. doi: 10.1083/jcb.201311051 24590170

4. Kassan A, Herms A, Fernandez-Vidal A, Bosch M, Schieber NL, Reddy BJ, et al. Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains. J Cell Biol. 2013;203(6):985–1001. doi: 10.1083/jcb.201305142 24368806

5. Ghadially FN. Ultrastructural Pathology Of the Cell and Matrix: Butterworths-Heinemann, Boston; 1988.

6. Gomez-Ramos P, Asuncion Moran M. Ultrastructural localization of intraneuronal Abeta-peptide in Alzheimer disease brains. J Alzheimers Dis. 2007;11(1):53–9. 17361035

7. Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D, Nussbaum RL. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. J Biol Chem. 2002;277(8):6344–52. 11744721

8. Finsterer J, Loscher W, Quasthoff S, Wanschitz J, Auer-Grumbach M, Stevanin G. Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. J Neurol Sci. 2012;318(1–2):1–18. doi: 10.1016/j.jns.2012.04.012 22560872

9. Reid E, Rugarli EI. In: Valle Beaudet, Vogelstein Kinzler, Antonarakis Ballabio, editors. Scriver’s Online Metabolic and Molecular Bases of Inherited Diseases. 2010. New York (New York): McGraw-Hill Medical.

10. Bruyn RP. The neuropathology of hereditary spastic paraparesis. Clin Neurol Neurosurg. 1992;94 Suppl:S16–8. 1320499

11. Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genet. 1999;23 : 296–303. 10610178

12. Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, et al. Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001;29(3):326–31. 11685207

13. Zuchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM, et al. Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006;79(2):365–9. 16826527

14. Errico A, Ballabio A, Rugarli EI. Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics. Hum Mol Genet. 2002;11(2):153–63. 11809724

15. Evans KJ, Gomes ER, Reisenweber SM, Gundersen GG, Lauring BP. Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing. J Cell Biol. 2005;168(4):599–606. 15716377

16. Roll-Mecak A, Vale RD. The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules. Curr Biol. 2005;15(7):650–5. 15823537

17. Allison R, Lumb JH, Fassier C, Connell JW, Ten Martin D, Seaman MN, et al. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome. J Cell Biol. 2013;202(3):527–43. doi: 10.1083/jcb.201211045 23897888

18. Connell JW, Lindon C, Luzio JP, Reid E. Spastin couples microtubule severing to membrane traffic in completion of cytokinesis and secretion. Traffic. 2009;10(1):42–56. doi: 10.1111/j.1600-0854.2008.00847.x 19000169

19. Riano E, Martignoni M, Mancuso G, Cartelli D, Crippa F, Toldo I, et al. Pleiotropic effects of spastin on neurite growth depending on expression levels. J Neurochem. 2009;108(5):1277–88. doi: 10.1111/j.1471-4159.2009.05875.x 19141076

20. Yang D, Rismanchi N, Renvoise B, Lippincott-Schwartz J, Blackstone C, Hurley JH. Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B. Nat Struct Mol Biol. 2008;15(12):1278–86. doi: 10.1038/nsmb.1512 18997780

21. Yu W, Qiang L, Solowska JM, Karabay A, Korulu S, Baas PW. The Microtubule-severing Proteins Spastin and Katanin Participate Differently in the Formation of Axonal Branches. Mol Biol Cell. 2008;19(4):1485–98. doi: 10.1091/mbc.E07-09-0878 18234839

22. Claudiani P, Riano E, Errico A, Andolfi G, Rugarli EI. Spastin subcellular localization is regulated through usage of different translation start sites and active export from the nucleus. Exp Cell Res. 2005;309(2):358–69. 16026783

23. Mancuso G, Rugarli EI. A cryptic promoter in the first exon of the SPG4 gene directs the synthesis of the 60-kDa spastin isoform. BMC Biol. 2008;6 : 31. doi: 10.1186/1741-7007-6-31 18613979

24. Park SH, Zhu PP, Parker RL, Blackstone C. Hereditary spastic paraplegia proteins REEP1, spastin, and atlastin-1 coordinate microtubule interactions with the tubular ER network. J Clin Invest. 2010;120(4):1097–110. doi: 10.1172/JCI40979 20200447

25. Hu J, Shibata Y, Zhu PP, Voss C, Rismanchi N, Prinz WA, et al. A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell. 2009;138(3):549–61. doi: 10.1016/j.cell.2009.05.025 19665976

26. Orso G, Pendin D, Liu S, Tosetto J, Moss TJ, Faust JE, et al. Homotypic fusion of ER membranes requires the dynamin-like GTPase atlastin. Nature. 2009;460(7258):978–83. doi: 10.1038/nature08280 19633650

27. Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci. 2012;35 : 25–47. doi: 10.1146/annurev-neuro-062111-150400 22540978

28. Klemm RW, Norton JP, Cole RA, Li CS, Park SH, Crane MM, et al. A conserved role for atlastin GTPases in regulating lipid droplet size. Cell Rep. 2013;3(5):1465–75. doi: 10.1016/j.celrep.2013.04.015 23684613

29. Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, et al. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002;31(4):347–8. 12134148

30. Eastman SW, Yassaee M, Bieniasz PD. A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J Cell Biol. 2009;184(6):881–94. doi: 10.1083/jcb.200808041 19307600

31. Renvoise B, Stadler J, Singh R, Bakowska JC, Blackstone C. Spg20-/ -⁠ mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Hum Mol Genet. 2012;21(16):3604–18. doi: 10.1093/hmg/dds191 22619377

32. Cartwright BR, Goodman JM. Seipin: from human disease to molecular mechanism. J Lipid Res. 2012;53(6):1042–55. doi: 10.1194/jlr.R023754 22474068

33. Tesson C, Nawara M, Salih MA, Rossignol R, Zaki MS, Al Balwi M, et al. Alteration of Fatty-Acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012;91(6):1051–64. doi: 10.1016/j.ajhg.2012.11.001 23176821

34. Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ, Ben-Salem S, de Bot ST, Nijhof B, et al. Mutations in DDHD2, Encoding an Intracellular Phospholipase A(1), Cause a Recessive Form of Complex Hereditary Spastic Paraplegia. Am J Hum Genet. 2012;91(6):1073–81. doi: 10.1016/j.ajhg.2012.10.017 23176823

35. Inloes JM, Hsu KL, Dix MM, Viader A, Masuda K, Takei T, et al. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. Proc Natl Acad Sci U S A. 2014;111(41):14924–9. doi: 10.1073/pnas.1413706111 25267624

36. Sanderson CM, Connell JW, Edwards TL, Bright NA, Duley S, Thompson A, et al. Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. Hum Mol Genet. 2006;15(2):307–18. 16339213

37. Reid E, Connell J, Edwards TL, Duley S, Brown SE, Sanderson CM. The hereditary spastic paraplegia protein spastin interacts with the ESCRT-III complex-associated endosomal protein CHMP1B. Hum Mol Genet. 2005;14(1):19–38. 15537668

38. Bulankina AV, Deggerich A, Wenzel D, Mutenda K, Wittmann JG, Rudolph MG, et al. TIP47 functions in the biogenesis of lipid droplets. J Cell Biol. 2009;185(4):641–55. doi: 10.1083/jcb.200812042 19451273

39. Ingelmo-Torres M, Gonzalez-Moreno E, Kassan A, Hanzal-Bayer M, Tebar F, Herms A, et al. Hydrophobic and basic domains target proteins to lipid droplets. Traffic. 2009;10(12):1785–801. doi: 10.1111/j.1600-0854.2009.00994.x 19874557

40. Solowska JM, Morfini G, Falnikar A, Himes BT, Brady ST, Huang D, et al. Quantitative and functional analyses of spastin in the nervous system: implications for hereditary spastic paraplegia. J Neurosci. 2008;28(9):2147–57. doi: 10.1523/JNEUROSCI.3159-07.2008 18305248

41. Orso G, Martinuzzi A, Rossetto MG, Sartori E, Feany M, Daga A. Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. J Clin Invest. 2005;115(11):3026–34. 16276413

42. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118(2):401–15. 8223268

43. Kammermeier L, Spring J, Stierwald M, Burgunder JM, Reichert H. Identification of the Drosophila melanogaster homolog of the human spastin gene. Dev Genes Evol. 2003;213(8):412–5. 12908108

44. Trotta N, Orso G, Rossetto MG, Daga A, Broadie K. The hereditary spastic paraplegia gene, spastin, regulates microtubule stability to modulate synaptic structure and function. Curr Biol. 2004;14(13):1135–47. 15242610

45. Stork T, Engelen D, Krudewig A, Silies M, Bainton RJ, Klambt C. Organization and function of the blood-brain barrier in Drosophila. J Neurosci. 2008;28(3):587–97. doi: 10.1523/JNEUROSCI.4367-07.2008 18199760

46. Matsushita-Ishiodori Y, Yamanaka K, Ogura T. The C. elegans homologue of the spastic paraplegia protein, spastin, disassembles microtubules. Biochem Biophys Res Commun. 2007;359(1):157–62. 17531954

47. Piomelli D, Astarita G, Rapaka R. A neuroscientist's guide to lipidomics. Nat Rev Neurosci. 2007;8(10):743–54. 17882252

48. Lucken-Ardjomande Hasler S, Vallis Y, Jolin HE, McKenzie AN, McMahon HT. GRAF1a is a brain-specific protein that promotes lipid droplet clustering and growth, and is enriched at lipid droplet junctions. J Cell Sci. 2014;127(21):4602–19. doi: 10.1242/jcs.147694 25189622

49. Andersson L, Bostrom P, Ericson J, Rutberg M, Magnusson B, Marchesan D, et al. PLD1 and ERK2 regulate cytosolic lipid droplet formation. J Cell Sci. 2006;119(Pt 11):2246–57. 16723731

50. Bostrom P, Rutberg M, Ericsson J, Holmdahl P, Andersson L, Frohman MA, et al. Cytosolic lipid droplets increase in size by microtubule-dependent complex formation. Arterioscler Thromb Vasc Biol. 2005;25(9):1945–51. 16051877

51. Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, et al. Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol. 2008;180(3):473–82. doi: 10.1083/jcb.200711136 18250201

52. Szymanski KM, Binns D, Bartz R, Grishin NV, Li WP, Agarwal AK, et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A. 2007;104(52):20890–5. 18093937

53. Tian Y, Bi J, Shui G, Liu Z, Xiang Y, Liu Y, et al. Tissue-autonomous function of Drosophila seipin in preventing ectopic lipid droplet formation. PLoS Genet. 2011;7(4):e1001364. doi: 10.1371/journal.pgen.1001364 21533227

54. Beilstein F, Bouchoux J, Rousset M, Demignot S. Proteomic analysis of lipid droplets from Caco-2/TC7 enterocytes identifies novel modulators of lipid secretion. PLoS ONE. 2013;8(1):e53017. doi: 10.1371/journal.pone.0053017 23301014

55. Larsson S, Resjo S, Gomez MF, James P, Holm C. Characterization of the lipid droplet proteome of a clonal insulin-producing beta-cell line (INS-1 832/13). J Proteome Res. 2012;11(2):1264–73. doi: 10.1021/pr200957p 22268682

56. Ding Y, Wu Y, Zeng R, Liao K. Proteomic profiling of lipid droplet-associated proteins in primary adipocytes of normal and obese mouse. Acta Biochim Biophys Sin (Shanghai). 2012;44(5):394–406. doi: 10.1093/abbs/gms008 22343379

57. Zhang H, Wang Y, Li J, Yu J, Pu J, Li L, et al. Proteome of skeletal muscle lipid droplet reveals association with mitochondria and apolipoprotein a-I. J Proteome Res. 2011;10(10):4757–68. doi: 10.1021/pr200553c 21870882

58. Brasaemle DL, Dolios G, Shapiro L, Wang R. Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. J Biol Chem. 2004;279(45):46835–42. 15337753

59. Thiele C, Spandl J. Cell biology of lipid droplets. Curr Opin Cell Biol. 2008;20(4):378–85. doi: 10.1016/j.ceb.2008.05.009 18606534

60. Wilfling F, Wang H, Haas JT, Krahmer N, Gould TJ, Uchida A, et al. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev Cell. 2013;24(4):384–99. doi: 10.1016/j.devcel.2013.01.013 23415954

61. Welte MA. Proteins under new management: lipid droplets deliver. Trends Cell Biol. 2007;17(8):363–9. 17766117

62. Hooper C, Puttamadappa SS, Loring Z, Shekhtman A, Bakowska JC. Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets. BMC biology. 2010;8 : 72. doi: 10.1186/1741-7007-8-72 20504295

63. Zehmer JK, Huang Y, Peng G, Pu J, Anderson RG, Liu P. A role for lipid droplets in inter-membrane lipid traffic. Proteomics. 2009;9(4):914–21. doi: 10.1002/pmic.200800584 19160396

64. Errico A, Claudiani P, D'Addio M, Rugarli EI. Spastin interacts with the centrosomal protein NA14, and is enriched in the spindle pole, the midbody and the distal axon. Hum Mol Genet. 2004;13(18):2121–32. 15269182

65. Qi D, Scholthof KB. A one-step PCR-based method for rapid and efficient site-directed fragment deletion, insertion, and substitution mutagenesis. J Virol Methods. 2008;149(1):85–90. doi: 10.1016/j.jviromet.2008.01.002 18314204

66. Cashman NR, Durham HD, Blusztajn JK, Oda K, Tabira T, Shaw IT, et al. Neuroblastoma x spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev Dyn. 1992;194(3):209–21. 1467557

67. Palanker L, Tennessen JM, Lam G, Thummel CS. Drosophila HNF4 regulates lipid mobilization and beta-oxidation. Cell Metab. 2009;9(3):228–39. doi: 10.1016/j.cmet.2009.01.009 19254568

68. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77(1):71–94. 4366476

69. Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, Gotta M, et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature. 2003;421(6920):231–7. 12529635

70. O'Rourke EJ, Soukas AA, Carr CE, Ruvkun G. C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab. 2009;10(5):430–5. doi: 10.1016/j.cmet.2009.10.002 19883620