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Chemico-Biological Interactions Transport of Lipids by ABC Proteins

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Chemico-Biological Interactions Transport of Lipids by ABC Proteins Chemico-Biological Interactions 180 (2009) 327–339 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Mini review Transport of lipids by ABC proteins: Interactions and implications for cellular toxicity, viability and function Irving L.M.H. Aye 1, Ambika T. Singh 1, Jeffrey A. Keelan ∗ School of Women’s and Infant’s Health, University of Western Australia, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, Perth, WA 6008, Australia article info abstract Article history: Members of the ATP-binding cassette (ABC) family of membrane-bound transporters are involved in mul- Received 9 December 2008 tiple aspects of transport and redistribution of various lipids and their conjugates. Most ABC transporters Received in revised form 15 April 2009 localize to the plasma membrane; some are associated with liquid-ordered cholesterol-/sphingolipid-rich Accepted 24 April 2009 microdomains, and to a lesser extent the membranes of the Golgi and endoplasmic reticulum. Hence, ABC Available online 6 May 2009 transporters are well placed to regulate plasma membrane lipid composition and the efflux and redistri- bution of structural phospholipids and sphingolipids during periods of cellular stress and recovery. ABC Keywords: transporters can also modulate cellular sensitivity to extrinsic pro-apoptotic signals through regulation of ABC transporters Phospholipids sphingomyelin–ceramide biosynthesis and metabolism. The functionality of ABC transporters is, in turn, Sphingolipids modulated by the lipid content of the microdomains in which they reside. Cholesterol, a major mem- Ceramide brane microdomain component, is not only a substrate of several ABC transporters, but also regulates Cholesterol ABC activity through its effects on microdomain structure. Several important bioactive lipid mediators Apoptosis and toxic lipid metabolites are also effluxed by ABC transporters. In this review, the complex interactions between ABC transporters and their lipid/sterol substrates will be discussed and analyzed in the context of their relevance to cellular function, toxicity and apoptosis. © 2009 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction ......................................................................................................................................... 328 2. Endogenous lipid substrates of ABC transporters................................................................................................... 328 2.1. Mechanism of lipid efflux .................................................................................................................... 328 2.2. ABC efflux of cholesterol and other sterols .................................................................................................. 330 2.2.1. ABCA family ........................................................................................................................ 330 2.2.2. ABCG family ........................................................................................................................ 331 2.2.3. Sterol transport by other ABC proteins ............................................................................................ 331 2.3. Phospholipid efflux .......................................................................................................................... 331 2.4. Efflux and trafficking of sphingolipids ...................................................................................................... 332 2.4.1. ABCB1/MDR1 ....................................................................................................................... 332 2.4.2. ABCC1/MRP1....................................................................................................................... 332 2.4.3. ABCA family ........................................................................................................................ 332 3. Effects of membrane lipids on ABC transporter activity ............................................................................................ 332 3.1. Membrane microdomains (lipid rafts) and ABC activity .................................................................................... 332 3.1.1. MDR1 ............................................................................................................................... 332 3.1.2. ABCA1.............................................................................................................................. 333 3.1.3. ABCG family ........................................................................................................................ 333 3.2. Sphingolipid regulation of ABC transporter function ....................................................................................... 333 4. Transport of pro-apoptotic lipids by ABC transporters ............................................................................................. 334 4.1. MDR1 ......................................................................................................................................... 334 ∗ Corresponding author. Tel.: +61 8 9340 1880; fax: +61 8 9381 3031. E-mail address: [email protected] (J.A. Keelan). 1 Both authors contributed equally. 0009-2797/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2009.04.012 328 I.L.M.H. Aye et al. / Chemico-Biological Interactions 180 (2009) 327–339 4.2. ABCG2 ........................................................................................................................................ 334 4.3. Oxysterol transport .......................................................................................................................... 334 4.4. Phagocytosis ................................................................................................................................. 334 5. Summary and conclusions .......................................................................................................................... 334 Conflict of interest .................................................................................................................................. 335 Acknowledgements ................................................................................................................................ 335 References ........................................................................................................................................... 335 1. Introduction in trafficking of hydrophobic drugs have the ability to transport analogs of membrane lipids [35]. Following the identification of The mammalian ATP-binding cassette (ABC) superfamily con- a role for the archetypal drug transporters MDR1 and MDR3 in sists of 49 individual transport proteins belonging to 7 sub-families phospholipid efflux [36,37], many of the aforementioned ABC drug (ABCA to ABCG) involved in translocating a wide range of substrates transporters have also been implicated in lipid transport [35,38,39]. across cellular membranes [1–4]. While ABC proteins are typically In addition, many of the more recently identified members, par- localized in the plasma membrane, some are also expressed in intra- ticularly from the ABCA and ABCG subfamilies, have been identi- cellular membranes of the Golgi, mitochondria and endoplasmic fied as key molecules in the regulation of cellular lipid transport reticulum [4–8]. ABC transporters mediate ATP-driven transmem- and whole body lipid homeostasis (Table 1). What is more, evi- brane efflux against a concentration gradient of a wide variety of dence now suggests that the function of many of these proteins is, amphiphilic ligands, including glycolipids, phospholipids, sterols in turn, dependent on the membrane lipid milieu in which they and xenobiotics [4,9,10]. As such, they participate in diverse bio- reside. logical processes such as waste disposal and detoxification, cell The lipid bilayer of the plasma membrane is made up of asym- signaling, lipid trafficking, membrane homeostasis, drug resistance metrically arranged lipid species [40]. This asymmetric distribu- and stem cell development [11,12]. tion is usually preserved throughout the cellular life but in cer- Members of the ABC superfamily show extensive sequence tain circumstances, such as during cell differentiation or apoptosis, homology and conservation of domain organization [13,14]. Func- asymmetry is lost through facilitated phospholipid translocation tional ABC proteins typically comprise of two transmembrane or endo-/exocytosis and related processes. Transbilayer movement domains and two ATP-binding domains. Substrate specificity is of lipids is actively orchestrated by three major groups of enzymes: determined by 5 or 6 ␣-helices yielding anywhere between P-type ATPases (flippases), ABC transporters (floppases) and scram- 5 and 17 transmembrane segments. While most ABC proteins blases/lipid translocases (Fig. 1) [41,42]. In addition, certain reg- exist as full transporters, several members (mainly from the G- ulatory molecules have been postulated to co-exist with various subfamily) have only 1 transmembrane domain and 1 nucleotide lipid translocases to assist with their transport functions [43]. Con- binding fold and are therefore known as “half-transporters” [15]. sequently, disruption of the membrane equilibrium due to lateral These half-transporters form homo/hetero-oligomers to function movement of lipids across
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