Abstract
Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid.
Graphic abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- ABHD:
-
α/β-Hydrolase domain
- CMC:
-
Critical micellar concentration
- CNS:
-
Central nervous system
- CoA:
-
Coenzyme-A
- ConA:
-
Concanavalin A
- DAG:
-
Diacylglycerol
- ER:
-
Endoplasmic reticulum
- GPCR:
-
G-Protein-coupled Receptors
- GPS:
-
Glycero-phospho-L-serine
- HPLC:
-
High performance liquid chromatography
- LC–MS:
-
Liquid chromatography coupled to mass spectrometry
- MAG:
-
Monoacylglycerol
- MBOAT:
-
Membrane-bound O-acyl-transferase
- MRM:
-
Multiple reaction monitoring
- PA:
-
Phosphatidic acid
- PC:
-
Phosphatidylcholine
- PE:
-
Phosphatidylethanolamine
- PHARC:
-
Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract
- PI:
-
Phosphatidylinositol
- PS:
-
Phosphatidylserine
- S1P:
-
Sphingosine 1-phosphate
- TAG:
-
Triacylglycerol
- VLC:
-
Very long chain
References
Ahonen TJ, Savinainen JR, Yli-Kauhaluoma J, Kalso E, Laitinen JT, Moreira VM (2018) Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A. ACS Med Chem Lett 9:1269–1273. https://doi.org/10.1021/acsmedchemlett.8b00442
Aoki J, Inoue A, Makide K, Saiki N, Arai H (2007) Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family. Biochimie 89:197–204. https://doi.org/10.1016/j.biochi.2006.09.021
Aoki J, Nagai Y, Hosono H, Inoue K, Arai H (2002) Structure and function of phosphatidylserine-specific phospholipase A1. Biochim Biophys Acta 1582:26–32
Barnes MJ, Cyster JG (2018) Lysophosphatidylserine suppression of T-cell activation via GPR174 requires. Galphas proteins Immunol Cell Biol 96:439–445. https://doi.org/10.1111/imcb.12025
Barnes MJ, Li CM, Xu Y, An J, Huang Y, Cyster JG (2015) The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function. J Exp Med 212:1011–1020
Bedard A, Tremblay P, Chernomoretz A, Vallieres L (2007) Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia 55:777–789. https://doi.org/10.1002/glia.20477
Bellini F, Bruni A (1993) Role of a serum phospholipase A1 in the phosphatidylserine-induced T cell inhibition. FEBS Lett 316:1–4. https://doi.org/10.1016/0014-5793(93)81724-e
Blankman JL, Long JZ, Trauger SA, Siuzdak G, Cravatt BF (2013) ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenrative disease PHARC. Proc Natl Acad Sci USA 110:1500–1505
Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356. https://doi.org/10.1016/j.chembiol.2007.11.006
Bruni A, Bigon E, Battistella A, Boarato E, Mietto L, Toffano G (1984) Lysophosphatidylserine as histamine releaser in mice and rats. Agents Actions 14:619–625. https://doi.org/10.1007/BF01978896
Bruni A, Bigon E, Boarato E, Mietto L, Leon A, Toffano G (1982) Interaction between nerve growth factor and lysophosphatidylserine on rat peritoneal mast cells. FEBS Lett 138:190–192. https://doi.org/10.1016/0014-5793(82)80438-9
Burke JE, Dennis EA (2009a) Phospholipase A2 biochemistry. Cardiovasc Drugs Ther 23:49–59. https://doi.org/10.1007/s10557-008-6132-9
Burke JE, Dennis EA (2009b) Phospholipase A2 structure/function, mechanism, and signaling. J Lipid Res 50(Suppl):S237–242. https://doi.org/10.1194/jlr.R800033-JLR200
Camara K, Kamat SS, Lasota CC, Cravatt BF, Howell AR (2015) Combining cross-metathesis and activity-based protein profiling: new beta-lactone motifs for targeting serine hydrolases. Bioorg Med Chem Lett 25:317–321. https://doi.org/10.1016/j.bmcl.2014.11.038
Caselli E, Baricordi OR, Melchiorri L, Bellini F, Ponzin D, Bruni A (1992a) Inhibition of DNA synthesis in peripheral blood mononuclear cells treated with phosphatidylserines containing unsaturated acyl chains. Immunopharmacology 23:205–213. https://doi.org/10.1016/0162-3109(92)90027-a
Caselli E, Bellini F, Ponzin D, Baricordi OR, Bruni A (1992b) Role of protein kinase C in the phosphatidylserine-induced inhibition of DNA synthesis in blood mononuclear cells. Immunopharmacology 24:191–201. https://doi.org/10.1016/0162-3109(92)90075-n
Chakravarty N, Goth A, Sen P (1973) Potentiation of dextran-induced histamine release from rat mast cells by phosphatidyl serine. Acta Physiol Scand 88:469–480. https://doi.org/10.1111/j.1748-1716.1973.tb05476.x
Chang HW, Inoue K, Bruni A, Boarato E, Toffano G (1988) Stereoselective effects of lysophosphatidylserine in rodents. Br J Pharmacol 93:647–653. https://doi.org/10.1111/j.1476-5381.1988.tb10322.x
Chen DH et al (2013) Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. Hum Mutat 34:1672–1678
Cho EY, Yun CH, Chae HZ, Chae HJ, Ahn T (2008) Lysophosphatidylserine-induced functional switch of human cytochrome P450 1A2 and 2E1 from monooxygenase to phospholipase D. Biochem Biophys Res Commun 376:584–589. https://doi.org/10.1016/j.bbrc.2008.09.023
Chu X et al (2013) An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease. J Med Genet 50:479–485. https://doi.org/10.1136/jmedgenet-2013-101595
Contos JJA, Ishii I, Chun J (2000) Lysophosphatidic acid receptors. Mol Pharm 58:1188–1196
Criscuolo C et al (2013) Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts (PHARC) screening in an Italian population. Eur J Neurol 20:e60. https://doi.org/10.1111/ene.12056
Doran AC, Yurdagul A Jr, Tabas I (2020) Efferocytosis in health and disease. Nat Rev Immunol 20:254–267. https://doi.org/10.1038/s41577-019-0240-6
Eisenberger T et al (2012) Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3. Orphanet J Rare Dis 7:59. https://doi.org/10.1186/1750-1172-7-59
Elliott MR, Koster KM, Murphy PS (2017) Efferocytosis signaling in the regulation of macrophage inflammatory responses. J Immunol 198:1387–1394. https://doi.org/10.4049/jimmunol.1601520
Fahy E, Sud M, Cotter D, Subramaniam S (2007) LIPID MAPS online tools for lipid research. Nucleic Acids Res 35:W606–612. https://doi.org/10.1093/nar/gkm324
Falorni A, Brozzetti A, Perniola R (2016) From Genetic predisposition to molecular mechanisms of autoimmune primary adrenal insufficiency. Front Horm Res 46:115–132. https://doi.org/10.1159/000443871
Fiskerstrand T et al (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Genet 87:410–417
Fiskerstrand T, Knappskog P, Majewski J, Wanders RJ, Boman H, Bindoff LA (2009) A novel Refsum-like disorder that maps to chromosome 20. Neurology 72:20–27
Frasch SC et al (2008) NADPH oxidase-dependent generation of lysophosphatidylserine enhances clearance of activated and dying neutrophils via G2A. J Biol Chem 283:33736–33749. https://doi.org/10.1074/jbc.M807047200
Frasch SC, Bratton DL (2012) Emerging roles for lysophosphatidylserine in resolution of inflammation. Prog Lipid Res 51:199–207
Frasch SC et al (2013) Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine. J Biol Chem 288:4583–4593. https://doi.org/10.1074/jbc.M112.438507
Frasch SC et al (2011) Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. J Biol Chem 286:12108–12122. https://doi.org/10.1074/jbc.M110.181800
Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63:1256–1272. https://doi.org/10.1124/mol.63.6.1256
Gijon MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR (2008) Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem 283:30235–30245. https://doi.org/10.1074/jbc.M806194200
Goldsmith DP, Mushett CW (1954) Studies of lipide anticoagulants. II. Isolation procedures. J Biol Chem 211:169–181
Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H (2014) S1P signaling: new therapies and opportunities. F1000Prime Rep 6:109. https://doi.org/10.12703/P6-109
Hashidate-Yoshida T et al (2015) Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport. Elife. https://doi.org/10.7554/eLife.06328
Hauser AS, Attwood MM, Rask-Andersen M, Schioth HB, Gloriam DE (2017) Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16:829–842. https://doi.org/10.1038/nrd.2017.178
Hishikawa D, Hashidate T, Shimizu T, Shindou H (2014) Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells. J Lipid Res 55:799–807. https://doi.org/10.1194/jlr.R046094
Hishikawa D, Shindou H, Kobayashi S, Nakanishi H, Taguchi R, Shimizu T (2008) Discovery essential of a lysophospholipid acyltransferase family for membrane asymmetry and diversity. Proc Natl Acad Sci USA 105:2830–2835. https://doi.org/10.1073/pnas.0712245105
Holub BJ (1980) The biosynthesis of phosphatidylserines by acylation of 1-acyl-sn-glycero-3-phosphoserine in rat liver. Biochim Biophys Acta 618:255–262. https://doi.org/10.1016/0005-2760(80)90031-4
Hoover HS, Blankman JL, Niessen S, Cravatt BF (2008) Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett 18:5838–5841. https://doi.org/10.1016/j.bmcl.2008.06.091
Horigome K, Tamori-Natori Y, Inoue K, Nojima S (1986) Effect of serine phospholipid structure on the enhancement of concanavalin A-induced degranulation in rat mast cells. J Biochem 100:571–579. https://doi.org/10.1093/oxfordjournals.jbchem.a121748
Hosono H et al (2001) Phosphatidylserine-specific phospholipase A1 stimulates histamine release from rat peritoneal mast cells through production of 2-acyl-1-lysophosphatidylserine. J Biol Chem 276:29664–29670. https://doi.org/10.1074/jbc.M104597200
Hwang SM, Kim HJ, Kim SM, Jung Y, Park SW, Chung IY (2018) Lysophosphatidylserine receptor P2Y10: A G protein-coupled receptor that mediates eosinophil degranulation. Clin Exp Allergy 48:990–999. https://doi.org/10.1111/cea.13162
Ichu TA et al (2020) ABHD12 and LPCAT3 Interplay regulates a lyso-phosphatidylserine-c20:4 phosphatidylserine lipid network implicated in neurological disease. Biochemistry. https://doi.org/10.1021/acs.biochem.0c00292
Iida Y et al (2014) Lysophosphatidylserine stimulates chemotactic migration of colorectal cancer cells through GPR34 and PI3K/Akt pathway. Anticancer Res 34:5465–5472
Ikubo M et al (2015) Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174. J Med Chem 58:4204–4219. https://doi.org/10.1021/jm5020082
Inoue A et al (2012) TGFalpha shedding assay: an accurate and versatile method for detecting GPCR activation. Nat Methods 9:1021–1029
Ishii I, Fukushima N, Ye X, Chun J (2004) Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 73:321–354
Iwashita M et al (2009) Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative. J Med Chem 52:5837–5863. https://doi.org/10.1021/jm900598m
Janssens S, Beyaert R (2003) Role of Toll-like receptors in pathogen recognition. Clin Microbiol Rev 16:637–646. https://doi.org/10.1128/cmr.16.4.637-646.2003
Jin ZT et al (2015) G-protein coupled receptor 34 knockdown impairs the proliferation and migration of HGC-27 gastric cancer cells in vitro. Chin Med J (Engl) 128:545–549. https://doi.org/10.4103/0366-6999.151114
Joshi A, Shaikh M, Singh S, Rajendran A, Mhetre A, Kamat SS (2018) Biochemical characterization of the PHARC-associated serine hydrolase ABHD12 reveals its preference for very-long-chain lipids. J Biol Chem 293:16953–16963. https://doi.org/10.1074/jbc.RA118.005640
Kabarowski JH, Feramisco JD, Le LQ, Gu JL, Luoh SW, Simon MI, Witte ON (2000) Direct genetic demonstration of G alpha 13 coupling to the orphan G protein-coupled receptor G2A leading to RhoA-dependent actin rearrangement. Proc Natl Acad Sci U S A 97:12109–12114. https://doi.org/10.1073/pnas.97.22.12109
Kabarowski JH, Zhu K, Le LQ, Witte ON, Xu Y (2001) Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science 293:702–705. https://doi.org/10.1126/science.1061781
Kalyvas A et al (2009) Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis. Brain 132:1221–1235. https://doi.org/10.1093/brain/awp002
Kamat SS et al (2015) Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay. Nat Chem Biol 11:164–171. https://doi.org/10.1038/nchembio.1721
Kathman SG, Boshart J, Jing H, Cravatt BF (2020) Blockade of the lysophosphatidylserine lipase ABHD12 potentiates ferroptosis in cancer cells. ACS Chem Biol 15:871–877. https://doi.org/10.1021/acschembio.0c00086
Katritch V, Cherezov V, Stevens RC (2013) Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol 53:531–556. https://doi.org/10.1146/annurev-pharmtox-032112-135923
Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461. https://doi.org/10.3389/fimmu.2014.00461
Kelkar DS et al (2019) A chemical-genetic screen identifies ABHD12 as an oxidized-phosphatidylserine lipase. Nat Chem Biol 15:169–178. https://doi.org/10.1038/s41589-018-0195-0
Kitamura H et al (2012) GPR34 is a receptor for lysophosphatidylserine with a fatty acid at the sn-2 position. J Biochem-Tokyo 151:511–518. https://doi.org/10.1093/jb/mvs011
Kobilka BK (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta 1768:794–807. https://doi.org/10.1016/j.bbamem.2006.10.021
Kolster L, Jensen C, Bruni A, Mietto L, Toffano G, Norn S (1987) Effect of lysophosphatidylserine on immunological histamine release. Biochim Biophys Acta 927:196–202. https://doi.org/10.1016/0167-4889(87)90135-2
Konkel JE et al (2017) Transforming growth factor-beta signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 46:660–674. https://doi.org/10.1016/j.immuni.2017.03.015
Kurano M et al (2015) Blood levels of serotonin are specifically correlated with plasma lysophosphatidylserine among the glycero-lysophospholipids. BBA Clin 4:92–98. https://doi.org/10.1016/j.bbacli.2015.08.003
Le LQ et al (2001) Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14:561–571. https://doi.org/10.1016/s1074-7613(01)00145-5
Lee SY et al (2008) Lysophosphatidylserine stimulates chemotactic migration in U87 human glioma cells. Biochem Biophys Res Commun 374:147–151. https://doi.org/10.1016/j.bbrc.2008.06.117
Liebscher I et al (2011) Altered immune response in mice deficient for the G protein-coupled receptor GPR34. J Biol Chem 286:2101–2110. https://doi.org/10.1074/jbc.M110.196659
Lin P, Ye RD (2003) The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis. J Biol Chem 278:14379–14386. https://doi.org/10.1074/jbc.M209101200
Lloret S, Moreno JJ (1995) Ca2+ influx, phosphoinositide hydrolysis, and histamine release induced by lysophosphatidylserine in mast cells. J Cell Physiol 165:89–95
Long C, Penny IF (1957) The structure of the naturally occurring phosphoglycerides. III. Action of moccasin-venom phospholipase A on ovolecithin and related substances. Biochem J 65:382–389. https://doi.org/10.1042/bj0650382
Long JZ, Cravatt BF (2011) The metabolic serine hydrolases and their functions in mammalian physiology and disease. Chem Rev 111:6022–6063
Lord CC, Thomas G, Brown JM (2013) Mammalian alpha beta hydrolase domain (ABHD) proteins: lipid metabolizing enzymes at the interface of cell signaling and energy metabolism. Biochim Biophys Acta 1831:792–802. https://doi.org/10.1016/j.bbalip.2013.01.002
Mallik S, Prasad R, Bhattacharya A, Sen P (2018) Synthesis of phosphatidylserine and its stereoisomers: their role in activation of blood coagulation. ACS Med Chem Lett 9:434–439. https://doi.org/10.1021/acsmedchemlett.8b00008
Martin CJ, Peters KN, Behar SM (2014) Macrophages clean up: efferocytosis and microbial control. Curr Opin Microbiol 17:17–23. https://doi.org/10.1016/j.mib.2013.10.007
Martin TW, Lagunoff D (1979) Interactions of lysophospholipids and mast cells. Nature 279:250–252. https://doi.org/10.1038/279250a0
Matsuda S et al (2008) Member of the membrane-bound O-acyltransferase (MBOAT) family encodes a lysophospholipid acyltransferase with broad substrate specificity. Genes Cells 13:879–888. https://doi.org/10.1111/j.1365-2443.2008.01212.x
Mietto L, Battistella A, Toffano G, Bruni A (1984) Modulation of lysophosphatidylserine-dependent histamine release. Agents Actions 14:376–378. https://doi.org/10.1007/BF01973832
Murakami M, Kudo I, Fujimori Y, Suga H, Inoue K (1991) Group II phospholipase A2 inhibitors suppressed lysophosphatidylserine-dependent degranulation of rat peritoneal mast cells. Biochem Biophys Res Commun 181:714–721. https://doi.org/10.1016/0006-291x(91)91249-c
Murakami M, Shimbara S, Kambe T, Kuwata H, Winstead MV, Tischfield JA, Kudo I (1998) The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2. J Biol Chem 273:14411–14423. https://doi.org/10.1074/jbc.273.23.14411
Murakami M, Shiraishi A, Tabata K, Fujita N (2008) Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor. Biochem Biophys Res Commun 371:707–712. https://doi.org/10.1016/j.bbrc.2008.04.145
Murakami N, Yokomizo T, Okuno T, Shimizu T (2004) G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem 279:42484–42491. https://doi.org/10.1074/jbc.M406561200
Mushett CW, Goldsmith DP, Kelley KL (1954) Studies on lipide anticoagulants. I. Assays in vitro. J Biol Chem 211:163–168
Nagai Y, Aoki J, Sato T, Amano K, Matsuda Y, Arai H, Inoue K (1999) An alternative splicing form of phosphatidylserine-specific phospholipase A1 that exhibits lysophosphatidylserine-specific lysophospholipase activity in humans. J Biol Chem 274:11053–11059. https://doi.org/10.1074/jbc.274.16.11053
Napier C, Mitchell AL, Gan E, Wilson I, Pearce SHS (2015) Role of the X-linked gene GPR174 in autoimmune Addison's disease. J Clin Endocr Metab 100:E187–E190. https://doi.org/10.1210/jc.2014-2694
Napier C, Mitchell AL, Gan EH, Wilson I, Pearce SHS (2014) Female proclivity to autoimmune addison’s disease: role of the X-linked gene GPR174. Endocr Rev 35:S1–S5
Nardini M, Dijkstra BW (1999) Alpha/beta hydrolase fold enzymes: the family keeps growing. Curr Opin Struct Biol 9:732–737. https://doi.org/10.1016/s0959-440x(99)00037-8
Navia-Paldanius D, Savinainen JR, Laitinen JT (2012) Biochemical and pharmacological characterization of human alpha/beta-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12). J Lipid Res 53:2413–2424. https://doi.org/10.1194/jlr.M030411
Nishiguchi KM et al (2014) Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration. Ophthalmology 121:1620–1627. https://doi.org/10.1016/j.ophtha.2014.02.008
Obinata H, Hattori T, Nakane S, Tatei K, Izumi T (2005) Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. J Biol Chem 280:40676–40683. https://doi.org/10.1074/jbc.M507787200
Ogasawara D, Ichu TA, Jing H, Hulce JJ, Reed A, Ulanovskaya OA, Cravatt BF (2019) Discovery and optimization of selective and in vivo active inhibitors of the lysophosphatidylserine lipase alpha/beta-hydrolase domain-containing 12 (ABHD12). J Med Chem 62:1643–1656. https://doi.org/10.1021/acs.jmedchem.8b01958
Ogasawara D et al (2018) Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat Chem Biol 14:1099–1108. https://doi.org/10.1038/s41589-018-0155-8
Okudaira M et al (2014) Separation and quantification of 2-acyl-1-lysophospholipids and 1-acyl-2-lysophospholipids in biological samples by LC-MS/MS. J Lipid Res 55:2178–2192. https://doi.org/10.1194/jlr.D048439
Ollis DL et al (1992) The alpha/beta hydrolase fold. Protein Eng 5:197–211. https://doi.org/10.1093/protein/5.3.197
Park KS, Lee HY, Kim MK, Shin EH, Bae YS (2005) Lysophosphatidylserine stimulates leukemic cells but not normal leukocytes. Biochem Biophys Res Commun 333:353–358
Park KS et al (2006) Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. Mol Pharmacol 69:1066–1073. https://doi.org/10.1124/mol.105.018960
Parker LC, Prince LR, Sabroe I (2007) Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin Exp Immunol 147:199–207. https://doi.org/10.1111/j.1365-2249.2006.03203.x
Pathak D, Mehendale N, Singh S, Mallik R, Kamat SS (2018) Lipidomics suggests a new role for ceramide synthase in phagocytosis. ACS Chem Biol 13:2280–2287. https://doi.org/10.1021/acschembio.8b00438
Peter C et al (2008) Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A. J Biol Chem 283:5296–5305. https://doi.org/10.1074/jbc.M706586200
Preissler J et al (2015) Altered microglial phagocytosis in GPR34-deficient mice. Glia 63:206–215. https://doi.org/10.1002/glia.22744
Rathbone L (1962) Some observations on the chromatographic behaviour of phosphatidylserine. Biochem J 85:461–466. https://doi.org/10.1042/bj0850461
Rathbone L, Magee WL, Thompson RH (1962) The preparation and properties of lysophosphatidylserine. Biochem J 83:498–502. https://doi.org/10.1042/bj0830498
Rathbone L, Maroney PM (1963) Preparation of phosphatidylserine. Nature 200:887–888. https://doi.org/10.1038/200887a0
Richmond GS, Smith TK (2011) Phospholipases A(1). Int J Mol Sci 12:588–612. https://doi.org/10.3390/ijms12010588
Rikitake Y et al (2002) Expression of G2A, a receptor for lysophosphatidylcholine, by macrophages in murine, rabbit, and human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 22:2049–2053. https://doi.org/10.1161/01.atv.0000040598.18570.54
Riley JF (1953a) Histamine in tissue mast cells. Science 118:332. https://doi.org/10.1126/science.118.3064.332
Riley JF (1953b) The relationship of the tissue mast cells to the blood vessels in the rat. J Pathol Bacteriol 65:461–469. https://doi.org/10.1002/path.1700650218
Riley JF, West GB (1953) The presence of histamine in tissue mast cells. J Physiol 120:528–537. https://doi.org/10.1113/jphysiol.1953.sp004915
Rivera R, Chun J (2008) Biological effects of lysophospholipids. Rev Physiol Biochem Pharmacol 160:25–46
Robert R, Mackay CR (2018) Galphas-coupled GPCRs GPR65 and GPR174. Downers for immune responses. Immunol Cell Biol 96:341–343. https://doi.org/10.1111/imcb.12027
Rong X et al (2013) LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab 18:685–697. https://doi.org/10.1016/j.cmet.2013.10.002
Rong X et al (2015) Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion. Elife. https://doi.org/10.7554/eLife.06557
Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5:560–570. https://doi.org/10.1038/nri1650
Rosen H, Gonzalez-Cabrera PJ, Sanna MG, Brown S (2009) Sphingosine 1-phosphate receptor signaling. Annu Rev Biochem 78:743–768
Rosen H, Liao J (2003) Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm. Curr Opin Chem Biol 7:461–468
Rosen H, Stevens RC, Hanson M, Roberts E, Oldstone MB (2013) Sphingosine-1-phosphate and its receptors: structure, signaling, and influence. Annu Rev Biochem 82:637–662
Rosenbaum DM, Rasmussen SG, Kobilka BK (2009) The structure and function of G-protein-coupled receptors. Nature 459:356–363. https://doi.org/10.1038/nature08144
Saghatelian A, Cravatt BF (2005a) Assignment of protein function in the postgenomic era. Nat Chem Biol 1:130–142. https://doi.org/10.1038/nchembio0805-130
Saghatelian A, Cravatt BF (2005b) Discovery metabolite profiling—forging functional connections between the proteome and metabolome. Life Sci 77:1759–1766. https://doi.org/10.1016/j.lfs.2005.05.019
Savinainen JR et al (2014) Biochemical and pharmacological characterization of the human lymphocyte antigen B-associated transcript 5 (BAT5/ABHD16A). PLoS ONE 9:e109869. https://doi.org/10.1371/journal.pone.0109869
Sayama M et al (2017) Probing the hydrophobic binding pocket of G-protein-coupled lysophosphatidylserine receptor GPR34/LPS1 by docking-aided structure-activity analysis. J Med Chem 60:6384–6399. https://doi.org/10.1021/acs.jmedchem.7b00693
Sayama M, Uwamizu A, Otani Y, Inoue A, Aoki J, Sekijima M, Ohwada T (2020) Membrane phospholipid analogues as molecular rulers to probe the position of the hydrophobic contact point of lysophospholipid ligands on the surface of G-protein-coupled receptor during membrane approach. Biochemistry 59:1173–1201. https://doi.org/10.1021/acs.biochem.0c00061
Sayo A et al (2019) GPR34 in spinal microglia exacerbates neuropathic pain in mice. J Neuroinflammation 16:82. https://doi.org/10.1186/s12974-019-1458-8
Shindou H, Hishikawa D, Harayama T, Eto M, Shimizu T (2013) Generation of membrane diversity by lysophospholipid acyltransferases. J Biochem-Tokyo 154:21–28. https://doi.org/10.1093/jb/mvt048
Shinjo Y et al (2017) Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174. Biochem Biophys Res Commun 494:332–338. https://doi.org/10.1016/j.bbrc.2017.10.028
Silver MJ, Turner DL, Holburn RR, Tocantins LM (1959) Anticoagulant activity of phosphatidylserine free of lysophosphatidylserine. Proc Soc Exp Biol Med 100:692–695. https://doi.org/10.3181/00379727-100-24746
Singh S, Joshi A, Kamat SS (2020) Mapping the neuroanatomy of ABHD16A-ABHD12 & lysophosphatidylserines provides new insights into the pathophysiology of the human neurological disorder PHARC. Biochemistry. https://doi.org/10.1021/acs.biochem.0c00349
Smith GA, Hesketh TR, Plumb RW, Metcalfe JC (1979) The exogenous lipid requirement for histamine release from rat peritoneal mast cells stimulated by concanavalin A. FEBS Lett 105:58–62. https://doi.org/10.1016/0014-5793(79)80887-x
Spies T, Blanck G, Bresnahan M, Sands J, Strominger JL (1989a) A new cluster of genes within the human major histocompatibility complex. Science 243:214–217
Spies T, Bresnahan M, Strominger JL (1989b) Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B. Proc Natl Acad Sci U S A 86:8955–8958
Sud M et al (2007) LMSD: LIPID MAPS structure database. Nucleic Acids Res 35:D527–532. https://doi.org/10.1093/nar/gkl838
Sugita K, Yamamura C, Tabata K, Fujita N (2013) Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP. Biochem Biophys Res Commun 430:190–195. https://doi.org/10.1016/j.bbrc.2012.11.046
Sugo T et al (2006) Identification of a lysophosphatidylserine receptor on mast cells. Biochem Biophys Res Commun 341:1078–1087. https://doi.org/10.1016/j.bbrc.2006.01.069
Szymanski K et al (2014) rs3827440, a nonsynonymous single nucleotide polymorphism within GPR174 gene in X chromosome, is associated with Graves' disease in Polish Caucasian population. Tissue Antigens 83:41–44. https://doi.org/10.1111/tan.12259
Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14. https://doi.org/10.1093/intimm/dxh186
Tamori-Natori Y, Horigome K, Inoue K, Nojima S (1986) Metabolism of lysophosphatidylserine, a potentiator of histamine release in rat mast cells. J Biochem 100:581–590. https://doi.org/10.1093/oxfordjournals.jbchem.a121749
Uwamizu A et al (2015) Lysophosphatidylserine analogues differentially activate three LysoPS receptors. J Biochem 157:151–160. https://doi.org/10.1093/jb/mvu060
van der Kleij D et al (2002) A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates toll-like receptor 2 and affects immune polarization. J Biol Chem 277:48122–48129
Vance JE (2015) Phospholipid synthesis and transport in mammalian cells. Traffic 16:1–18. https://doi.org/10.1111/tra.12230
Wang B et al (2016) Intestinal phospholipid remodeling is required for dietary-lipid uptake and survival on a high-fat diet. Cell Metab 23:492–504. https://doi.org/10.1016/j.cmet.2016.01.001
Wang L, Radu CG, Yang LV, Bentolila LA, Riedinger M, Witte ON (2005) Lysophosphatidylcholine-induced surface redistribution regulates signaling of the murine G protein-coupled receptor G2A. Mol Biol Cell 16:2234–2247. https://doi.org/10.1091/mbc.e04-12-1044
Wortmann SB et al (2015) Inborn errors of metabolism in the biosynthesis and remodelling of phospholipids. J Inherit Metab Dis 38:99–110. https://doi.org/10.1007/s10545-014-9759-7
Wu C, Jin X, Tsueng G, Afrasiabi C, Su AI (2016) BioGPS: building your own mash-up of gene annotations and expression profiles. Nucleic Acids Res 44:D313–316. https://doi.org/10.1093/nar/gkv1104
Wu C et al (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10:R130. https://doi.org/10.1186/gb-2009-10-11-r130
Yan CY et al. (2020) Candidate gene associations reveal sex-specific Graves’ disease risk alleles among Chinese Han populations. Mol Genet Genom Med 8:e1249. https://doi.org/10.1002/mgg3.1249
Yea K et al (2009) Lysophosphatidylserine regulates blood glucose by enhancing glucose transport in myotubes and adipocytes. Biochem Biophys Res Commun 378:783–788. https://doi.org/10.1016/j.bbrc.2008.11.122
Yoshimura H, Hashimoto T, Murata T, Fukushima K, Sugaya A, Nishio SY, Usami S (2015) Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness. Ann Otol Rhinol Laryngol 124(Suppl 1):77S–83S
Yu W et al (2013) Upregulation of GPR34 expression affects the progression and prognosis of human gastric adenocarcinoma by PI3K/PDK1/AKT pathway. Histol Histopathol 28:1629–1638. https://doi.org/10.14670/HH-28.1629
Zhang QY et al (2020) Genetic study in a large cohort supported different pathogenesis of graves' disease and hashimoto's hypothyroidism. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgaa170
Zhao R et al (2020) A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. Nature 577:416–420. https://doi.org/10.1038/s41586-019-1873-0
Zhao SX et al (2013) Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis. Hum Mol Genet 22:3347–3362. https://doi.org/10.1093/hmg/ddt183
Zuo B et al (2015) G-protein coupled receptor 34 activates Erk and phosphatidylinositol 3-kinase/Akt pathways and functions as alternative pathway to mediate p185Bcr-Abl-induced transformation and leukemogenesis. Leukemia Lymphoma 56:2170–2181. https://doi.org/10.3109/10428194.2014.981177
Acknowledgements
We thank Shubham Singh (IISER Pune) for critical comments and thoughtful discussions on this review. This work was supported by the DBT/Wellcome Trust India Alliance Fellowship [Grant Number IA/I/15/2/502058] to S.S.K.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Shanbhag, K., Mhetre, A., Khandelwal, N. et al. The Lysophosphatidylserines—An Emerging Class of Signalling Lysophospholipids. J Membrane Biol 253, 381–397 (2020). https://doi.org/10.1007/s00232-020-00133-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-020-00133-2