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J. Biol. Chem., Vol. 280, Issue 51, 42325-42335, December 23, 2005

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Regulated Localization of Rab18 to Lipid Droplets

EFFECTS OF LIPOLYTIC STIMULATION AND INHIBITION OF LIPID DROPLET CATABOLISM^*

Sally Martin1, Kim Driessen, Susan J. Nixon, Marino Zerial, and Robert G. Parton

From the Institute for Molecular Bioscience & Centre for Microscopy and Microanalysis, University of Queensland, Brisbane, Queensland 4072, Australia and the Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

Rab GTPases are crucial regulators of membrane traffic. Here we have examined a possible association of Rab proteins with lipid droplets (LDs), neutral lipid-containing organelles surrounded by a phospholipid monolayer, also known as lipid bodies, which have been traditionally considered relatively inert storage organelles. Although we found close apposition between LDs and endosomal compartments labeled by expressed Rab5, Rab7, or Rab11 constructs, there was no detectable labeling of the LD surface itself by these Rab proteins. In contrast, GFP-Rab18 localized to LDs and immunoelectron microscopy showed direct association with the monolayer surface. Green fluorescent protein (GFP)-Rab18-labeled LDs underwent oscillatory movements in a localized area as well as sporadic, rapid, saltatory movements both in the periphery of the cell and toward the perinuclear region. In both adipocytes and non-adipocyte cell lines Rab18 localized to a subset of LDs. To gain insights into this specific localization, Rab18 was co-expressed with Cav3^DGV, a truncation mutant of caveolin-3 shown to inhibit the catabolism and motility of lipid droplets. GFP-Rab18 and mRFP-Cav3^DGV labeled mutually exclusive subpopulations of LDs. Moreover, in 3T3-L1 adipocytes, stimulation of lipolysis increased the localization of Rab18 to LDs, an effect reversed by -adrenergic antagonists. These results show that a Rab protein localizes directly to the monolayer surface of LDs. In addition, association with the LD surface was increased following stimulation of lipolysis and inhibited by a caveolin mutant suggesting that recruitment of Rab18 is regulated by the metabolic state of individual LDs.

Received for publication, June 20, 2005 , and in revised form, September 15, 2005.

^* This work was supported by a grant from the National Health and Medical Research Council of Australia (to R. G. P.). Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology, established with funding from the ACRF. Electron microscopy was performed at the Centre for Microscopy and Microanalysis at the University of Queensland. The IMB is a Special Research Centre of the Australian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental videos 1-5.

¹ To whom correspondence should be addressed. Tel.: 61-7-3346-2030; Fax: 61-7-3346-2101; E-mail: s.martin{at}imb.uq.edu.au.

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