Arf1/COPI Machinery Acts Directly on Lipid Droplets and Enables Their Connection to the ER for Protein Targeting

Overview

Journal Elife

Specialty Biology

Date 2014 Feb 6

PMID 24497546

Citations 144

Authors

Florian Wilfling

Abdou Rachid Thiam

Maria-Jesus Olarte

Jing Wang

Rainer Beck

Travis J Gould

Edward S Allgeyer

Frederic Pincet

Jorg Bewersdorf

Robert V Farese Jr

Tobias C Walther

Affiliations

Soon will be listed here.

Abstract

Lipid droplets (LDs) are ubiquitous organelles that store neutral lipids, such as triacylglycerol (TG), as reservoirs of metabolic energy and membrane precursors. The Arf1/COPI protein machinery, known for its role in vesicle trafficking, regulates LD morphology, targeting of specific proteins to LDs and lipolysis through unclear mechanisms. Recent evidence shows that Arf1/COPI can bud nano-LDs (∼60 nm diameter) from phospholipid-covered oil/water interfaces in vitro. We show that Arf1/COPI proteins localize to cellular LDs, are sufficient to bud nano-LDs from cellular LDs, and are required for targeting specific TG-synthesis enzymes to LD surfaces. Cells lacking Arf1/COPI function have increased amounts of phospholipids on LDs, resulting in decreased LD surface tension and impairment to form bridges to the ER. Our findings uncover a function for Arf1/COPI proteins at LDs and suggest a model in which Arf1/COPI machinery acts to control ER-LD connections for localization of key enzymes of TG storage and catabolism. DOI: http://dx.doi.org/10.7554/eLife.01607.001.

Citing Articles

Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway.

Huda N, Kusumanchi P, Jiang Y, Gao H, Thoudam T, Zeng G Hepatol Commun. 2025; 9(3).

PMID: 39969435 PMC: 11841855. DOI: 10.1097/HC9.0000000000000641.

The evolving landscape of ER-LD contact sites.

Kumar A, Yadav S, Choudhary V Front Cell Dev Biol. 2024; 12:1483902.

PMID: 39421023 PMC: 11484260. DOI: 10.3389/fcell.2024.1483902.

Surface tension-driven sorting of human perilipins on lipid droplets.

Dias Araujo A, Bello A, Bigay J, Franckhauser C, Gautier R, Cazareth J J Cell Biol. 2024; 223(12).

PMID: 39297796 PMC: 11413419. DOI: 10.1083/jcb.202403064.

Roles of lipid droplets and related proteins in metabolic diseases.

Zhang Z, Yu Z, Liang D, Song K, Kong X, He M Lipids Health Dis. 2024; 23(1):218.

PMID: 39030618 PMC: 11264848. DOI: 10.1186/s12944-024-02212-y.

Evolutionary trajectory for nuclear functions of ciliary transport complex proteins.

Ewerling A, May-Simera H Microbiol Mol Biol Rev. 2024; 88(3):e0000624.

PMID: 38995044 PMC: 11426024. DOI: 10.1128/mmbr.00006-24.

References

Soni K, Mardones G, Sougrat R, Smirnova E, Jackson C, Bonifacino J . Coatomer-dependent protein delivery to lipid droplets. J Cell Sci. 2009; 122(Pt 11):1834-41. PMC: 2684835. DOI: 10.1242/jcs.045849. View

Bouvet S, Golinelli-Cohen M, Contremoulins V, Jackson C . Targeting of the Arf-GEF GBF1 to lipid droplets and Golgi membranes. J Cell Sci. 2013; 126(Pt 20):4794-805. DOI: 10.1242/jcs.134254. View

Brasaemle D, Wolins N . Packaging of fat: an evolving model of lipid droplet assembly and expansion. J Biol Chem. 2011; 287(4):2273-9. PMC: 3268387. DOI: 10.1074/jbc.R111.309088. View

Yang H, Hsu C, Yang J, Yang W . Monodansylpentane as a blue-fluorescent lipid-droplet marker for multi-color live-cell imaging. PLoS One. 2012; 7(3):e32693. PMC: 3291611. DOI: 10.1371/journal.pone.0032693. View

Hell S, Wichmann J . Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt Lett. 2009; 19(11):780-2. DOI: 10.1364/ol.19.000780. View

Folch J, Lees M, SLOANE STANLEY G . A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957; 226(1):497-509. View

Murugesan S, Goldberg E, Dou E, Brown W . Identification of diverse lipid droplet targeting motifs in the PNPLA family of triglyceride lipases. PLoS One. 2013; 8(5):e64950. PMC: 3669214. DOI: 10.1371/journal.pone.0064950. View

Bard F, Casano L, Mallabiabarrena A, Wallace E, Saito K, Kitayama H . Functional genomics reveals genes involved in protein secretion and Golgi organization. Nature. 2006; 439(7076):604-7. DOI: 10.1038/nature04377. View

Nickel W, Brugger B, Wieland F . Vesicular transport: the core machinery of COPI recruitment and budding. J Cell Sci. 2002; 115(Pt 16):3235-40. DOI: 10.1242/jcs.115.16.3235. View

10.

Dobrosotskaya I, Seegmiller A, Brown M, Goldstein J, Rawson R . Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science. 2002; 296(5569):879-83. DOI: 10.1126/science.1071124. View

11.

Beck R, Sun Z, Adolf F, Rutz C, Bassler J, Wild K . Membrane curvature induced by Arf1-GTP is essential for vesicle formation. Proc Natl Acad Sci U S A. 2008; 105(33):11731-6. PMC: 2575275. DOI: 10.1073/pnas.0805182105. View

12.

Kurat C, Wolinski H, Petschnigg J, Kaluarachchi S, Andrews B, Natter K . Cdk1/Cdc28-dependent activation of the major triacylglycerol lipase Tgl4 in yeast links lipolysis to cell-cycle progression. Mol Cell. 2009; 33(1):53-63. DOI: 10.1016/j.molcel.2008.12.019. View

13.

Manneville J, Casella J, Ambroggio E, Gounon P, Bertherat J, Bassereau P . COPI coat assembly occurs on liquid-disordered domains and the associated membrane deformations are limited by membrane tension. Proc Natl Acad Sci U S A. 2008; 105(44):16946-51. PMC: 2579358. DOI: 10.1073/pnas.0807102105. View

14.

Krahmer N, Farese Jr R, Walther T . Balancing the fat: lipid droplets and human disease. EMBO Mol Med. 2013; 5(7):973-83. PMC: 3721468. DOI: 10.1002/emmm.201100671. View

15.

Thiam A, Farese Jr R, Walther T . The biophysics and cell biology of lipid droplets. Nat Rev Mol Cell Biol. 2013; 14(12):775-86. PMC: 4526153. DOI: 10.1038/nrm3699. View

16.

Bartz R, Zehmer J, Zhu M, Chen Y, Serrero G, Zhao Y . Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation. J Proteome Res. 2007; 6(8):3256-65. DOI: 10.1021/pr070158j. View

17.

Stone S, Levin M, Zhou P, Han J, Walther T, Farese Jr R . The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J Biol Chem. 2008; 284(8):5352-61. PMC: 2643492. DOI: 10.1074/jbc.M805768200. View

18.

Guo Y, Walther T, Rao M, Stuurman N, Goshima G, Terayama K . Functional genomic screen reveals genes involved in lipid-droplet formation and utilization. Nature. 2008; 453(7195):657-61. PMC: 2734507. DOI: 10.1038/nature06928. View

19.

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. View

20.

Murphy S, Martin S, Parton R . Quantitative analysis of lipid droplet fusion: inefficient steady state fusion but rapid stimulation by chemical fusogens. PLoS One. 2011; 5(12):e15030. PMC: 3009727. DOI: 10.1371/journal.pone.0015030. View