Sphingolipid Signaling in Metabolic Disorders
2012; Cell Press; Volume: 16; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2012.06.017
ISSN1932-7420
AutoresTimothy Hla, Andrew J. Dannenberg,
Tópico(s)Lysosomal Storage Disorders Research
ResumoSphingolipids, ubiquitous membrane lipids in eukaryotes, carry out a myriad of critical cellular functions. The past two decades have seen significant advances in sphingolipid research, and in 2010 a first sphingolipid receptor modulator was employed as a human therapeutic. Furthermore, cellular signaling mechanisms regulated by sphingolipids are being recognized as critical players in metabolic diseases. This review focuses on recent advances in cellular and physiological mechanisms of sphingolipid regulation and how sphingolipid signaling influences metabolic diseases. Progress in this area may contribute to new understanding and therapeutic options in complex diseases such as atherosclerosis, diabetes, metabolic syndromes, and cancer. Sphingolipids, ubiquitous membrane lipids in eukaryotes, carry out a myriad of critical cellular functions. The past two decades have seen significant advances in sphingolipid research, and in 2010 a first sphingolipid receptor modulator was employed as a human therapeutic. Furthermore, cellular signaling mechanisms regulated by sphingolipids are being recognized as critical players in metabolic diseases. This review focuses on recent advances in cellular and physiological mechanisms of sphingolipid regulation and how sphingolipid signaling influences metabolic diseases. Progress in this area may contribute to new understanding and therapeutic options in complex diseases such as atherosclerosis, diabetes, metabolic syndromes, and cancer. Sphingolipids are eukaryotic specific lipids that carry out essential structural and functional roles (van Meer and Hoetzl, 2010van Meer G. Hoetzl S. Sphingolipid topology and the dynamic organization and function of membrane proteins.FEBS Lett. 2010; 584: 1800-1805Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). Within membranes sphingolipids are found associated with cholesterol, and together they help form lipid domains. Thus sphingolipids are necessary for the formation of specialized membrane domains such as rafts and caveolae. All eukaryotic cells have the capacity to produce sphingolipids via a de novo pathway in the endoplasmic reticulum (Bartke and Hannun, 2009Bartke N. Hannun Y.A. Bioactive sphingolipids: metabolism and function.J. Lipid Res. 2009; 50: S91-S96Crossref PubMed Scopus (0) Google Scholar). In this pathway, the amino acid serine is conjugated with the fatty acid palmitoyl CoA by the rate-limiting enzyme serine palmitoyl transferase (SPT). The product of the reaction, dihydrosphingosine (sphinganine), is further converted to dihydro ceramide, which is dehydrogenated into ceramide, a key intermediate. Specialized carrier proteins such as ceramide transfer protein (CERT) transport ceramide to the Golgi. Ceramide can follow several metabolic fates. For example, it can be glycosylated to form glycosphingolipids, phosphorylated into ceramide 1-phosphate, or acquire a polar head group to form sphingomyelin. SM and glycosphingolipids are stable, accumulate to high levels in cells, and are transported via vesicle-mediated mechanisms to specialized membrane domains. For example, sphingomyelin accumulates in the outer leaflet of the plasma membrane as a major constituent of rafts (Figure 1). The control of sphingolipid synthesis by cells is regulated by substrate availability as well as by other mechanisms related to lipid composition and membrane homeostasis (Bartke and Hannun, 2009Bartke N. Hannun Y.A. Bioactive sphingolipids: metabolism and function.J. Lipid Res. 2009; 50: S91-S96Crossref PubMed Scopus (0) Google Scholar; Breslow and Weissman, 2010Breslow D.K. Weissman J.S. Membranes in balance: mechanisms of sphingolipid homeostasis.Mol. Cell. 2010; 40: 267-279Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). The availability of the substrate palmitoyl CoA enhances the de novo synthesis of sphingolipids. Since free palmitate levels rise in obesity and metabolic excess, sphingolipid flux through the de novo pathway is enhanced (Bikman and Summers, 2011Bikman B.T. Summers S.A. Ceramides as modulators of cellular and whole-body metabolism.J. Clin. Invest. 2011; 121: 4222-4230Crossref PubMed Scopus (41) Google Scholar; Holland and Summers, 2008Holland W.L. Summers S.A. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism.Endocr. Rev. 2008; 29: 381-402Crossref PubMed Scopus (157) Google Scholar). Recently, the Orm family proteins, which inhibit the SPT enzymes, were found to control de novo sphingolipid synthesis (Breslow et al., 2010Breslow D.K. Collins S.R. Bodenmiller B. Aebersold R. Simons K. Shevchenko A. Ejsing C.S. Weissman J.S. Orm family proteins mediate sphingolipid homeostasis.Nature. 2010; 463: 1048-1053Crossref PubMed Scopus (126) Google Scholar) in the yeast S. cerevisiae. When sphingolipid levels are low, Orm proteins are highly phosphorylated by the protein kinase Ypk1, a yeast homolog of the mammalian serum and glucocorticoid-induced kinase. This modification blocks the ability of the Orm proteins to inhibit SPT enzyme complex in the ER and therefore enhances de novo sphingolipid synthesis (Roelants et al., 2011Roelants F.M. Breslow D.K. Muir A. Weissman J.S. Thorner J. Protein kinase Ypk1 phosphorylates regulatory proteins Orm1 and Orm2 to control sphingolipid homeostasis in Saccharomyces cerevisiae.Proc. Natl. Acad. Sci. USA. 2011; 108: 19222-19227Crossref PubMed Scopus (37) Google Scholar). Interestingly, Ypk1 kinase itself is activated by the protein kinase called target of rapamycin complex (TORC) 2 that can sense the membrane sphingolipid levels, especially ceramide (Aronova et al., 2008Aronova S. Wedaman K. Aronov P.A. Fontes K. Ramos K. Hammock B.D. Powers T. Regulation of ceramide biosynthesis by TOR complex 2.Cell Metab. 2008; 7: 148-158Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar; Dickson, 2008Dickson R.C. Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast.J. Lipid Res. 2008; 49: 909-921Crossref PubMed Scopus (81) Google Scholar). Recently, it was shown that sphingolipid depletion or plasma membrane stress in yeast (induced by mechanical stretching) activated translocation of the Slm1 protein to the Torc2 complex, activation of Torc2-dependent Ypk1 kinase, phosphorylation of Orm proteins, and stimulation of sphingolipid synthesis via SPT. It is thought that increased sphingolipids reduce membrane stress, and thus this system represents a homeostatic regulatory system for cellular membranes (Berchtold et al., 2012Berchtold D. Piccolis M. Chiaruttini N. Riezman I. Riezman H. Roux A. Walther T.C. Loewith R. Plasma membrane stress induces relocalization of Slm proteins and activation of TORC2 to promote sphingolipid synthesis.Nat. Cell Biol. 2012; 14: 542-547Crossref PubMed Scopus (29) Google Scholar) (Figure 2). Whether this signaling system regulates sphingolipid synthesis in vertebrates and metazoans is not known, but interestingly, regulation of the mTorc2-dependent Akt kinase (which is in the same AGC kinase family as the yeast Ypk1) is regulated by biomechanical forces in a caveolae-dependent manner (Yu et al., 2006Yu J. Bergaya S. Murata T. Alp I.F. Bauer M.P. Lin M.I. Drab M. Kurzchalia T.V. Stan R.V. Sessa W.C. Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels.J. Clin. Invest. 2006; 116: 1284-1291Crossref PubMed Scopus (132) Google Scholar). In mammalian cells, ceramide transport via the CERT protein also is sensitive to intracellular sphingolipid levels, which appear to regulate CERT function by PKD-dependent phosphorylation (Kumagai et al., 2007Kumagai K. Kawano M. Shinkai-Ouchi F. Nishijima M. Hanada K. Interorganelle trafficking of ceramide is regulated by phosphorylation-dependent cooperativity between the PH and START domains of CERT.J. Biol. Chem. 2007; 282: 17758-17766Crossref PubMed Scopus (39) Google Scholar). Therefore, cells appear to possess the machinery to couple membrane sphingolipid levels to the biosynthetic pathway at the level of the rate-limiting enzyme SPT as well as at other key regulatory steps. However, it is important to stress that our knowledge of regulation of sphingolipid metabolism is significantly limited compared to other lipid regulatory pathways, i.e., sterol metabolism. An extensive network of enzymes metabolize sphingolipids into bioactive lipid mediators (Milhas et al., 2010Milhas D. Clarke C.J. Hannun Y.A. Sphingomyelin metabolism at the plasma membrane: implications for bioactive sphingolipids.FEBS Lett. 2010; 584: 1887-1894Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) (Figure 1). For example, sphingomyelinase, which responds to extracellular signals, forms ceramide via a hydrolytic reaction. Ceramide is further converted to sphingosine by ceramidases. Sphingosine levels in cellular membranes are kept low in part due to the action of ceramide synthase and sphingosine kinases (Sphk1 and Sphk2), which phosphorylate it into sphingosine 1-phosphate (S1P). In vertebrates, S1P is secreted into the extracellular space by specific transporters, one of which, spinster 2 homolog-2 (Spns2), was recently characterized (Kawahara et al., 2009Kawahara A. Nishi T. Hisano Y. Fukui H. Yamaguchi A. Mochizuki N. The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors.Science. 2009; 323: 524-527Crossref PubMed Scopus (106) Google Scholar). In mammalian plasma, high levels of S1P are found, whereas interstitial fluids contain very low levels, thus forming a gradient of S1P in different compartments (Pappu et al., 2007Pappu R. Schwab S.R. Cornelissen I. Pereira J.P. Regard J.B. Xu Y. Camerer E. Zheng Y.W. Huang Y. Cyster J.G. Coughlin S.R. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.Science. 2007; 316: 295-298Crossref PubMed Scopus (327) Google Scholar) (Figure 3A). Both hematopoietic cells and vascular endothelial cells contribute to high plasma S1P (Pappu et al., 2007Pappu R. Schwab S.R. Cornelissen I. Pereira J.P. Regard J.B. Xu Y. Camerer E. Zheng Y.W. Huang Y. Cyster J.G. Coughlin S.R. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.Science. 2007; 316: 295-298Crossref PubMed Scopus (327) Google Scholar; Venkataraman et al., 2008Venkataraman K. Lee Y.M. Michaud J. Thangada S. Ai Y. Bonkovsky H.L. Parikh N.S. Habrukowich C. Hla T. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate.Circ. Res. 2008; 102: 669-676Crossref PubMed Scopus (146) Google Scholar), and lymphatic endothelial cells (Pham et al., 2010Pham T.H. Baluk P. Xu Y. Grigorova I. Bankovich A.J. Pappu R. Coughlin S.R. McDonald D.M. Schwab S.R. Cyster J.G. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning.J. Exp. Med. 2010; 207: 17-27Crossref PubMed Scopus (73) Google Scholar) are thought to secrete S1P for the lymphatic circulation. Acute liver failure strongly suppresses plasma S1P levels (Yong-Moon Lee and T.H., unpublished data). Further, production of HDL-associated ApoM, which chaperones S1P (see below) by the liver, may be important for high plasma S1P (Christoffersen et al., 2011Christoffersen C. Obinata H. Kumaraswamy S.B. Galvani S. Ahnström J. Sevvana M. Egerer-Sieber C. Muller Y.A. Hla T. Nielsen L.B. Dahlbäck B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.Proc. Natl. Acad. Sci. USA. 2011; 108: 9613-9618Crossref PubMed Scopus (56) Google Scholar). The action of Spns2 in vascular endothelium is important for maintaining high plasma S1P, as global knockout as well as endothelial-specific knockout of Spns2 resulted in significant decreases in plasma S1P (Fukuhara et al., 2012Fukuhara S. Simmons S. Kawamura S. Inoue A. Orba Y. Tokudome T. Sunden Y. Arai Y. Moriwaki K. Ishida J. et al.The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice.J. Clin. Invest. 2012; 122: 1416-1426Crossref PubMed Scopus (22) Google Scholar). ABCC1 was proposed to be the S1P transporter in mast cell lines (Mitra et al., 2006Mitra P. Oskeritzian C.A. Payne S.G. Beaven M.A. Milstien S. Spiegel S. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells.Proc. Natl. Acad. Sci. USA. 2006; 103: 16394-16399Crossref PubMed Scopus (186) Google Scholar); however, Abcc1 knockout mice did not show alterations in plasma S1P levels (Lee et al., 2007Lee Y.M. Venkataraman K. Hwang S.I. Han D.K. Hla T. A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC).Prostaglandins Other Lipid Mediat. 2007; 84: 154-162Crossref PubMed Scopus (52) Google Scholar). Thus, whether ABCC1 is a physiologically relevant S1P transporter is unclear and the mechanism by which S1P is transported from hematopoietic cells remains unknown. Since ABC transport inhibitors are nonspecific, much of the conclusions on S1P transport by this class of membrane proteins should be reassessed using more specific tools and/or genetic models. Plasma S1P is bound to HDL (∼65%) and albumin (∼30%). Interestingly, the ability of HDL to induce vasodilation, endothelial cell barrier function, cardioprotection, and endothelial cell migration is dependent on S1P (Nofer et al., 2004Nofer J.R. van der Giet M. Tölle M. Wolinska I. von Wnuck Lipinski K. Baba H.A. Tietge U.J. Gödecke A. Ishii I. Kleuser B. et al.HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3.J. Clin. Invest. 2004; 113: 569-581Crossref PubMed Scopus (0) Google Scholar; Sattler and Levkau, 2009Sattler K. Levkau B. Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection.Cardiovasc. Res. 2009; 82: 201-211Crossref PubMed Scopus (44) Google Scholar). These studies suggest that the beneficial property of HDL to reduce the risk of cardiovascular disease may in part depend on its S1P chaperoning function. The molecular details of how HDL carries S1P was elusive until recently. Apolipoprotein M (ApoM) binds to S1P (KD ∼1 μM), cocrystallizes with S1P, delivers S1P to its receptors, and is essential for S1P association with HDL in both mice and humans (Christoffersen et al., 2011Christoffersen C. Obinata H. Kumaraswamy S.B. Galvani S. Ahnström J. Sevvana M. Egerer-Sieber C. Muller Y.A. Hla T. Nielsen L.B. Dahlbäck B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.Proc. Natl. Acad. Sci. USA. 2011; 108: 9613-9618Crossref PubMed Scopus (56) Google Scholar). In Apom KO mice, endothelial barrier function was compromised even though significant plasma S1P was still present, associated with other plasma proteins such as albumin. It is currently unclear how HDL/ApoM complex interacts with cell surface S1P and HDL receptors. It is likely that S1P and HDL receptors cooperate upon HDL interaction with cell surfaces. In contrast to S1P, ceramide in plasma is associated mostly with VLDL and LDL (Khovidhunkit et al., 2004Khovidhunkit W. Kim M.S. Memon R.A. Shigenaga J.K. Moser A.H. Feingold K.R. Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.J. Lipid Res. 2004; 45: 1169-1196Crossref PubMed Scopus (477) Google Scholar). In addition, glycosphingolipids are also associated with LDL and VLDL (Nilsson and Duan, 2006Nilsson A. Duan R.D. Absorption and lipoprotein transport of sphingomyelin.J. Lipid Res. 2006; 47: 154-171Crossref PubMed Scopus (77) Google Scholar). The role of lipoprotein-associated sphingolipids in normal cardiovascular function and pathology is not well understood. It is likely that enrichment of sphingolipids in lipoproteins and cardiovascular cells contributes to the high abundance of S1P in the circulatory system. S1P is degraded by several enzymes. S1P phosphatases-1 and -2 as well as lyso phospholipid phosphatase 3 (LPP3) and S1P lyase are involved in the degradation of this lipid mediator (Blaho and Hla, 2011Blaho V.A. Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.Chem. Rev. 2011; 111: 6299-6320Crossref PubMed Scopus (16) Google Scholar; Bréart et al., 2011Bréart B. Ramos-Perez W.D. Mendoza A. Salous A.K. Gobert M. Huang Y. Adams R.H. Lafaille J.J. Escalante-Alcalde D. Morris A.J. Schwab S.R. Lipid phosphate phosphatase 3 enables efficient thymic egress.J. Exp. Med. 2011; 208: 1267-1278Crossref PubMed Scopus (23) Google Scholar) (Figure 1). The phosphatases convert S1P into sphingosine and thus feed back into the sphingolipid metabolic pathway. However, S1P lyase irreversibly degrades it into hexadecenal and phosphoethanolamine (Saba et al., 1997Saba J.D. Nara F. Bielawska A. Garrett S. Hannun Y.A. The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase.J. Biol. Chem. 1997; 272: 26087-26090Crossref PubMed Scopus (160) Google Scholar), which are intermediates in the phospholipid biosynthetic pathway. Recent work shows that further conversion of the highly reactive fatty aldehyde hexadecenal into hexadecenoic acid by hexadecenal dehydrogenase occurs in many cells. Since this ubiquitous pathway ultimately leads to the formation of palmitoyl CoA, it is important for conversion of sphingolipids to glycerolipids (Nakahara et al., 2012Nakahara K. Ohkuni A. Kitamura T. Abe K. Naganuma T. Ohno Y. Zoeller R.A. Kihara A. The Sjögren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway.Mol. Cell. 2012; 46: 461-471Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). Further details of S1P metabolism can be obtained in the following recent authoritative reviews: Bartke and Hannun, 2009Bartke N. Hannun Y.A. Bioactive sphingolipids: metabolism and function.J. Lipid Res. 2009; 50: S91-S96Crossref PubMed Scopus (0) Google Scholar; Bréart et al., 2011Bréart B. Ramos-Perez W.D. Mendoza A. Salous A.K. Gobert M. Huang Y. Adams R.H. Lafaille J.J. Escalante-Alcalde D. Morris A.J. Schwab S.R. Lipid phosphate phosphatase 3 enables efficient thymic egress.J. Exp. Med. 2011; 208: 1267-1278Crossref PubMed Scopus (23) Google Scholar; Cyster and Schwab, 2012Cyster J.G. Schwab S.R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.Annu. Rev. Immunol. 2012; 30: 69-94Crossref PubMed Scopus (56) Google Scholar; Maceyka et al., 2012Maceyka M. Harikumar K.B. Milstien S. Spiegel S. Sphingosine-1-phosphate signaling and its role in disease.Trends Cell Biol. 2012; 22: 50-60Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar. Although all eukaryotes, from single-celled yeast to complex multicellular organisms, possess the entire sphingolipid metabolic pathway, the extracellular appearance of S1P and its receptor-dependent signaling modes seem to be vertebrate specific (Blaho and Hla, 2011Blaho V.A. Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.Chem. Rev. 2011; 111: 6299-6320Crossref PubMed Scopus (16) Google Scholar). Indeed, S1P transporter and its G protein-coupled receptors are only present in the vertebrate genomes. There are five receptors for S1P, named as S1P1–S1P5. These receptors are closely related to lysophosphatidic acid and cannabinoid receptors and are encoded by five distinct genes (Hla and Brinkmann, 2011Hla T. Brinkmann V. Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation.Neurology. 2011; 76: S3-S8Crossref PubMed Scopus (51) Google Scholar; Hla et al., 2001Hla T. Lee M.J. Ancellin N. Paik J.H. Kluk M.J. Lysophospholipids—receptor revelations.Science. 2001; 294: 1875-1878Crossref PubMed Scopus (389) Google Scholar). They are expressed widely and couple to overlapping as well as distinct G proteins. Receptor signaling, cellular effects, and biological effects have been extensively discussed in several recent review articles (Blaho and Hla, 2011Blaho V.A. Hla T. Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.Chem. Rev. 2011; 111: 6299-6320Crossref PubMed Scopus (16) Google Scholar; Chun et al., 2010Chun J. Hla T. Lynch K.R. 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Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.Chem. Rev. 2011; 111: 6299-6320Crossref PubMed Scopus (16) Google Scholar; Cyster and Schwab, 2012Cyster J.G. Schwab S.R. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.Annu. Rev. Immunol. 2012; 30: 69-94Crossref PubMed Scopus (56) Google Scholar; Obinata and Hla, 2012Obinata H. Hla T. Sphingosine 1-phosphate in coagulation and inflammation.Semin. Immunopathol. 2012; 34: 73-91Crossref PubMed Scopus (19) Google Scholar). In the vascular system, S1P activation of its receptors regulates vascular tone, vascular permeability, angiogenesis, vascular hyperplasia after injury, atherosclerosis, and heart function. However, in the immune system, the S1P gradient is critical for egress of immune cells from secondary lymphoid organs into the circulatory system. Therefore, S1P receptor-dependent trafficking paradigms are critical for normal immune homeostasis as well as inflammatory situations that occur in autoimmune diseases. A unique aspect of S1P signaling is that the ligand is present in abundance for the cardiovascular and blood-borne cells (Hla et al., 2008Hla T. Venkataraman K. Michaud J. The vascular S1P gradient-cellular sources and biological significance.Biochim. Biophys. Acta. 2008; 1781: 477-482Crossref PubMed Scopus (63) Google Scholar; Schwab et al., 2005Schwab S.R. Pereira J.P. Matloubian M. Xu Y. Huang Y. Cyster J.G. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients.Science. 2005; 309: 1735-1739Crossref PubMed Scopus (323) Google Scholar). Given that the dissociation constants of ligand receptor interactions are in the low nanomolar range (Hla et al., 2001Hla T. Lee M.J. Ancellin N. Paik J.H. Kluk M.J. Lysophospholipids—receptor revelations.Science. 2001; 294: 1875-1878Crossref PubMed Scopus (389) Google Scholar; Lee et al., 1998Lee M.J. Van Brocklyn J.R. Thangada S. Liu C.H. Hand A.R. Menzeleev R. Spiegel S. Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.Science. 1998; 279: 1552-1555Crossref PubMed Scopus (667) Google Scholar), it is likely that cell surface receptors would be stimulated when exposed to plasma (total concentration of S1P in plasma is approximately 0.5–1 μM). Therefore, receptor expression and subcellular localization are key to bioactivity of S1P signaling in cells (Oo et al., 2011Oo M.L. Chang S.H. Thangada S. Wu M.T. Rezaul K. Blaho V. Hwang S.I. Han D.K. Hla T. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice.J. Clin. Invest. 2011; 121: 2290-2300Crossref PubMed Scopus (38) Google Scholar). Thus, a given cell with S1P receptors on the plasma membrane will receive a more robust intracellular signal than the cell in which the receptors are sequestered in intracellular organelles. Recently, an S1P receptor modulator called Fingolimod/Gilenya was approved for the treatment of multiple sclerosis in over 40 countries (Brinkmann et al., 2010Brinkmann V. Billich A. Baumruker T. Heining P. Schmouder R. Francis G. Aradhye S. Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis.Nat. Rev. Drug Discov. 2010; 9: 883-897Crossref PubMed Scopus (207) Google Scholar). It is a functional antagonist of the S1P1 receptor, by inducing irreversible internalization into endosomes, which makes the lymphocytes refractory to the S1P-dependent egress step from lymphoid organs. Thus, Fingolimod treatment leads to disrupted trafficking of autoreactive T cells and suppression of autoimmune CNS inflammation. S1P receptor-based therapeutics have entered the clinical era, and numerous efforts are being undertaken to further understand the biology of this lipid signaling pathway and to develop novel therapeutics in the control of various autoimmune and related diseases. Sphingolipid metabolism under normal cellular homeostasis is thought to be critical for fundamental cellular events such as membrane homeostasis, endocytosis, cell movement, nutrient transport, and protein synthesis (Hannun and Obeid, 2008Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (820) Google Scholar; Breslow and Weissman, 2010Breslow D.K. Weissman J.S. Membranes in balance: mechanisms of sphingolipid homeostasis.Mol. Cell. 2010; 40: 267-279Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). In addition, extracellular stimuli such as cytokines, hormones, and cell stress (X-ray, UV irradiation) perturb sphingolipid metabolism via effects on both de novo synthesis and degradation (Gault et al., 2010Gault C.R. Obeid L.M. Hannun Y.A. An overview of sphingolipid metabolism: from synthesis to breakdown.Adv. Exp. Med. Biol. 2010; 688: 1-23Crossref PubMed Scopus (75) Google Scholar; Morales et al., 2007Morales A. Lee H. Goñi F.M. Kolesnick R. Fernandez-Checa J.C. Sphingolipids and cell death.Apoptosis. 2007; 12: 923-939Crossref PubMed Scopus (106) Google Scholar; Stancevic and Kolesnick, 2010Stancevic B. Kolesnick R. Ceramide-rich platforms in transmembrane signaling.FEBS Lett. 2010; 584: 1728-1740Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar; Zeidan and Hannun, 2010Zeidan Y.H. Hannun Y.A. The acid sphingomyelinase/ceramide pathway: biomedical significance and mechanisms of regulation.Curr. Mol. Med. 2010; 10: 454-466Crossref PubMed Scopus (33) Google Scholar). This results in localized increases in ceramide levels. This hydrophobic sphingolipid induces aggregation of lipid domains and forms ceramide-rich macrodomains. Such domains are large (from >200 nm to several microns in diameter) and are thought to influence membrane signaling events as described below (Cremesti et al., 2001Cremesti A. Paris F. Grassmé H. Holler N. Tschopp J. Fuks Z. Gulbins E. Kolesnick R. Ceramide enables fas to cap and kill.J. Biol. Chem. 2001; 276: 23954-23961Crossref PubMed Scopus (240) Google Scholar; Grassmé et al., 2003Grassmé H. Cremesti A. Kolesnick R. Gulbins E. Ceramide-mediated clustering is required for CD95-DISC formation.Oncogene. 2003; 22: 5457-5470Crossref PubMed Scopus (149) Google Scholar). Since lipid rafts localize signaling proteins, it is likely that ceramide-induced formation of macrodomains would alter composition, clustering, and interaction of signaling proteins and/or lipids. Thus, alterations in ceramide levels likely influence lipid/lipid, protein/lipid, and protein/protein interactions within the membranes translating to transmission of intracellular signals. Further, it has been shown that ceramide can interact with a number of signaling proteins, such as kinase suppressor of ras (KSR), atypical protein kinase-C (Yin et al., 2009Yin X. Zafrullah M. Lee H. Haimovitz-Friedman A. Fuks Z. Kolesnick R. A ceramide-binding C1 domain mediates kinase suppressor of ras membrane translocation.Cell. Physiol. Biochem. 2009; 24: 219-230Crossref PubMed Scopus (21) Google Scholar; Zhang et al., 1997Zhang Y. Yao B. Delikat S. Bayoumy S. Lin X.H. Basu S. McGinley M. Chan-Hui P.Y. Lichenstein H. Kolesnick R. Kinase suppressor of Ras is ceramide-activated protein kinase.Cell. 1997; 89: 63-72Abstract Full Text Full Text PDF PubMed Google Scholar), c-Raf-1 (Basu et al., 1998Basu S. Bayoumy S. Zhang Y. Lozano J. Kolesnick R. BAD enables ceramide to signal apoptosis via Ras and Raf-1.J. Biol. Chem. 1998; 273: 30419-30426Crossref PubMed Scopus (135) Google Scholar), cathepsin D (Pettus et al., 2002Pettus B.J. Chalfant C.E. Hannun Y.A. Ceramide in apoptosis: an overview and current perspectives.Biochim. Biophys. Acta. 2002; 1585: 114-125Crossref PubMed Scopus (441) Google Scholar), and ceramide-activated protein phosphatase (Chalfant et al., 2004Chalfant C.E. Szulc Z. Roddy P. Bielawska A. Hannun Y.A. The structural requirements for ceramide activation of serine-threonine protein phosphatases.J. Lipid Res. 2004; 45: 496-506Crossref PubMed Scopus (65) Google Scholar; Dobrowsky et al., 1993Dobrowsky R.T. Kamibayashi C. Mumby M.C. Hannun Y.A. Ceramide activates heterotrimeric protein phosphatase 2A.J. Biol. Chem. 1993; 268: 15523-15530Abstract Full Text PDF PubMed Google Scholar). The physiological significance of such interactions remains to be further explored. In other words, it is not clear if such interactions occur in a classical second messenger mode, whereby lipid/protein interaction changes the activity and/or localization of a particular signaling prote
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