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Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions

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Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions CB28CH16-Valdivia ARI 5 September 2012 17:10 Emerging Roles for Lipid Droplets in Immunity and Host-Pathogen Interactions Hector Alex Saka and Raphael Valdivia Department of Molecular Genetics and Microbiology and Center for Microbial Pathogenesis, Duke University Medical Center, Durham, North Carolina 27710; email: [email protected] Annu. Rev. Cell Dev. Biol. 2012. 28:411–37 Keywords First published online as a Review in Advance on eicosanoids, interferon, autophagy May 11, 2012 The Annual Review of Cell and Developmental Abstract Biology is online at cellbio.annualreviews.org Lipid droplets (LDs) are neutral lipid storage organelles ubiquitous to Access provided by Duke University on 10/14/19. For personal use only. This article’s doi: eukaryotic cells. It is increasingly recognized that LDs interact exten- 10.1146/annurev-cellbio-092910-153958 sively with other organelles and that they perform functions beyond Annu. Rev. Cell Dev. Biol. 2012.28:411-437. Downloaded from www.annualreviews.org Copyright c 2012 by Annual Reviews. passive lipid storage and lipid homeostasis. One emerging function for All rights reserved LDs is the coordination of immune responses, as these organelles par- 1081-0706/12/1110-0411$20.00 ticipate in the generation of prostaglandins and leukotrienes, which are important inflammation mediators. Similarly, LDs are also beginning to be recognized as playing a role in interferon responses and in antigen cross presentation. Not surprisingly, there is emerging evidence that many pathogens, including hepatitis C and Dengue viruses, Chlamydia, and Mycobacterium, target LDs during infection either for nutritional purposes or as part of an anti-immunity strategy. We here review re- cent findings that link LDs to the regulation and execution of immune responses in the context of host-pathogen interactions. 411 CB28CH16-Valdivia ARI 5 September 2012 17:10 Zhang et al. 2010) and in bacteria such as Contents Mycobacterium, Rhodococcus, Nocardia, Strepto- myces,andAcinetobacter (Alvarez et al. 1996, INTRODUCTION TO LIPID Daniel et al. 2004, Kalscheuer & Steinbuchel DROPLETBIOLOGY............ 412 2003, Waltermann et al. 2005). Although tra- Background and Evolving Views of ditionally viewed as just passive depots of ex- the Mammalian Lipid Droplet . 412 cess fat, the discovery of several LD-associated Current Models for Lipid proteins with functions beyond lipid synthe- Droplet Biogenesis. 415 sis and storage has sparked interest among Functional Diversity cell biologists as to what additional function(s) of Lipid Droplets . 419 these organelles may play (Beckman 2006). Genome-Wide Approaches to Many recent outstanding reviews have cap- Understand Lipid Droplet tured the excitement in the cell biology com- Function....................... 419 munity as to how these organelles are gener- THE INTERSECTION ated and how proteins and lipids are trafficked OF LIPID DROPLETS AND to LDs (Brasaemle 2007; Brasaemle et al. 2009; PATHOGENS.................... 420 Fujimoto & Parton 2011; Fujimoto et al. 2008; Lipid Droplets as Assembly Farese & Walther 2009; Goodman 2008, 2009; Platforms for Hepatitis Greenberg & Coleman 2011; Greenberg et al. C Virus and Other Viruses . 420 2011; Guo et al. 2009; Kalantari et al. 2010; Intersection Between Lipid Droplets Thiele & Spandl 2008). However, the functions and Bacterial Pathogens . 421 LDs play beyond neutral lipid storage are not Lipid Droplet Interactions well understood. This problem is compounded with the Protozoan Pathogen by the observation that these are not homoge- Trypanosoma cruzi ............... 423 neous organelles (Murphy et al. 2009, Thiele & LIPID DROPLETS AS Spandl 2008); distinct populations of LDs likely MODULATORS OF IMMUNE exist, which may represent different stages in a RESPONSES..................... 423 maturation process or perhaps are distinct en- Lipid Droplets as Sites of tities that communicate with different cellular Eicosanoid and Inflammatory compartments. In addition, LDs also may per- Lipid Biosynthesis . 423 form different functions in different cell types Lipid Droplets as Sites of Assembly (Murphy et al. 2009). In this review, we ex- of Effectors of Interferon plore recent unexpected findings linking these Responses...................... 424 organelles to the regulation and execution of Access provided by Duke University on 10/14/19. For personal use only. An Emerging Role for Lipid immune responses. Droplets in Antigen Cross Annu. Rev. Cell Dev. Biol. 2012.28:411-437. Downloaded from www.annualreviews.org Presentation.................... 425 Lipid Droplets and Their Role Background and Evolving Views inAutophagy................... 426 of the Mammalian Lipid Droplet PERSPECTIVES.................... 428 LDs are spherical structures consisting mostly of triacylglycerols (TAGs) and sterol esters surrounded by a phospholipid monolayer (Tauchi-Sato et al. 2002) (Figure 1). In INTRODUCTION TO LIPID adipocytes, a large LD (∼200-μm diameter) DROPLET BIOLOGY can occupy most of the cell’s cytoplasm Lipid droplets (LDs) are neutral lipid-rich in- under conditions of excess lipids. In most tracellular organelles present in all eukaryotic other cell types, multiple LDs, ranging from cells (Murphy 2001, Reue 2011, Service 2009, 0.1- to approximately 5-μm diameter, are 412 Saka · Valdivia CB28CH16-Valdivia ARI 5 September 2012 17:10 a b EERR M LLDD c Rab18 PLIN TAG SE LD LLDD LD protein DAG PL monolayer 1 μm Figure 1 Lipid droplets (LDs) are neutral lipid-rich organelles surrounded by a phospholipid monolayer. (a,b) Transmission electron microscopy of HeLa cells treated with oleic acid. LDs are spherical, translucent structures that are often in close apposition to mitochondria (M) and endoplasmic reticulum (ER) membranes. (c) Schematic representation of a generic mammalian LD: a core of neutral lipids, mainly triacylglycerols (TAGs), sterol esters (SEs), and minor amounts of diacylglycerols (DAGs), is surrounded by a monolayer of phospholipids (PLs) and associated proteins. Among LD-associated proteins, the perilipin family (PLIN) of structural LDs and the Rab GTPase Rab18 are prominent. The number of LD-associated proteins may exceed 200, including lipid metabolic enzymes, SNARE proteins, ER-associated degradation components, and Rab proteins. evenly distributed throughout the cytoplasm. Phospholipids found in the LD monolayer Because LDs lack a phospholipid bilayer, primarily consist of phosphatidylcholine Access provided by Duke University on 10/14/19. For personal use only. these organelles are unlikely to follow classical (PC), phosphatidylethanolamine (PE), and vesicle-mediated membrane transport path- phosphatidylinositol; minor levels of lyso-PC, Annu. Rev. Cell Dev. Biol. 2012.28:411-437. Downloaded from www.annualreviews.org ways to receive or deliver protein and lipid lyso-PE, and cholesterol are also present (Bartz components. The neutral lipids that compose et al. 2007a, Prattes et al. 2000, Tauchi-Sato the core of LDs also vary depending on the cell et al. 2002). By mass spectrometry, more than type. For instance, in white adipocytes, TAGs 160 lipid species have been identified in LDs. are largely dominant, whereas in macrophage Notably, sphingomyelin, phosphatidylserine, foam cells, sterol esters are more abundant, and phosphatidic acid are relatively absent in and in yeast, TAGs and sterol esters contribute these organelles (Bartz et al. 2007a). equally (Bartz et al. 2007a, Leber et al. 1994, LDs are intimately linked to energy and Tauchi-Sato et al. 2002). Other lipids found lipid homeostasis: they expand in size and in the core of LDs include monoalk(en)yl number when excess lipids are present, which diacylglycerols and free cholesterol in low prevents lipotoxicity (Listenberger et al. 2003), levels (Bartz et al. 2007a, Hevonoja et al. 2000). and are rapidly consumed when carbon sources www.annualreviews.org • Lipid Droplets In Immunity 413 CB28CH16-Valdivia ARI 5 September 2012 17:10 are depleted and additional energy supplies are protein (ADRP), and tail-interacting protein required (Masuda et al. 2006). Peroxisomes and 47 (TIP47)], which groups the more abundant mitochondria can directly access the core lipids and best-characterized LD proteins (Brasaemle of LDs for β-oxidation of released fatty acids 2007). Members of this family (PLIN1 to 5) or to provide precursors for protein lipidation, (Kimmel et al. 2010) share a conserved PAT phospholipid biosynthesis, and membrane bio- domain and 11-mer repeats predicted to genesis (Binns et al. 2006, Murphy 2001, van form amphipathic helices; the extreme 100 Meer et al. 2008). Excess fatty acids acquired N-terminal amino acids are the most conserved from lipid transporters in the plasma mem- (Bussell & Eliezer 2003, Lu et al. 2001). brane, endocytosis of lipoprotein particles, or de Perilipin (PLIN1) is primarily expressed in novo synthesis in the cytoplasm can be esterified adipocytes and steroideogenic cells (Londos and incorporated into growing LDs (Brown et al. 1995) and was originally identified as a et al. 1979, McArthur et al. 1999, Stremmel target for protein kinase A–mediated phospho- et al. 2001). This exchange of lipids likely occurs rylation in lipolytically stimulated adipocytes at structures analogous to membrane contact (Greenberg et al. 1991). This was the first indi- sites that have been described between the cation that a protein coating the surface of LDs endoplasmic reticulum (ER) and mitochondria regulated neutral lipid metabolism. PLIN1 is (Levine 2004, Levine & Loewen 2006).
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