The ins and outs of phospholipid asymmetry in the plasma membrane: Roles in health and disease

Critical Reviews in Biochemistry and Molecular Biology

Volumn 44, Issue 5, 2009, Pages 264-277

  Fadeel, Bengt ^a   Xue, Ding ^b  

^a KAROLINSKA INSTITUTE   (Sweden)

^b UNIVERSITY OF COLORADO   (United States)

Author keywords

Aminophospholipid translocases; Caenhorhabditis elegans; Mitochondria; Phosphatidylserine; phospholipid scramblases; Phospholipid asymmetry; Programmed cell clearance

Indexed keywords

PHOSPHATIDYLSERINE; PHOSPHOLIPID;

APOPTOSIS; CELL MEMBRANE; ENDOPLASMIC RETICULUM; LIPID BILAYER; LIPID TRANSPORT; MAMMAL; MEMBRANE POTENTIAL; MITOCHONDRION; NONHUMAN; PRIORITY JOURNAL; REVIEW; ANIMAL; BIOPHYSICS; CHEMISTRY; HUMAN; METABOLISM; SIGNAL TRANSDUCTION;

EUKARYOTA; MAMMALIA;

ANIMALS; APOPTOSIS; BIOPHYSICAL PHENOMENA; CELL MEMBRANE; HUMANS; MITOCHONDRIA; PHOSPHOLIPIDS; SIGNAL TRANSDUCTION;

EID: 70349898677     PISSN: 10409238     EISSN: 15497798     Source Type: Journal    
DOI: 10.1080/10409230903193307     Document Type: Review

References (119)

1. Arroyo A, Modriansky M, Serinkan FB, Bello RI, Matsura T, Jiang J, Tyurin VA, Tyurina YY, Fadeel B and Kagan VE. 2002. NADPH oxidase-dependent oxidation and externalization of phos-phatidylserine during apoptosis in Me2SO-diferentiated HL-60 cells. Role in phagocytic clearance. J Biol Chem 277:49965-49975
2. Arur S, Uche UE, Rezaul K, Fong M, Scranton V, Cowan AE, Mohler W, and Han DK. 2003. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Dev Cell 4:587-598
3. Asano K, Miwa M, Miwa K, Hanayama R, Nagase H, Nagata S and Tanaka M. 2004. Masking of phosphatidylserine inhibits apop-totic cell engulfment and induces autoantibody production in mice. J Exp Med 200:459-467
4. Aussel C, Pelassy C and Breittmayer JP. 1998. CD95 (Fas/APO-1) induces an increased phosphatidylserine synthesis that precedes its externalization during programmed cell death. FEBS Lett 431:195-199
5. Bassé F, Stout JG, Sims PJ and Wiedmer T. 1996. Isolation of an erythrocyte membrane protein that mediates Ca2+-dependent transbilayer movement of phospholipid. J Biol Chem 271:17205-17210
6. Ben-Efraim I, Zhou Q, Wiedmer T, Gerace L and Sims PJ. 2004. Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated pathway and interacts with DNA. Biochemistry 43:3518-3526
7. Blom WM, de Bont HJ and Nagelkerke JF. 2003. Regional loss of the mitochondrial membrane potential in the hepatocyte is rapidly followed by externalization of phosphatidylserines at that spe-cifc site during apoptosis. J Biol Chem 278:12467-12474
8. Bodzioch M, Orso E, Klucken T, Langmann T, Böttcher L, Diederich W, Drobnik W, Barlage S, Büchler C, Porsch-Ozcürümez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ and Schmitz G. 1999. Te gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347-351
9. Böse J, Gruber AD, Helming L, Schiebe S, Wegener I, Hafner M, Beales M, Köntgen F and Lengeling A. 2004. Te phosphatidyl-serine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J Biol 3:15
10. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excofon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J and Hayden MR. 1999. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein defciency. Nat Genet 22:336-345
11. Buratta S, Migliorati G, Marchetti C, Mambrini R, Riccardi C and Mozzi R. 2000. Dexamethasone increases the incorporation of [3H]serine into phosphatidylserine and the activity of serine base exchange enzyme in mouse thymocytes: a possible relation between serine base exchange enzyme and apoptosis. Mol Cell Biochem 211:61-67
12. Chang MK, Bergmark C, Laurila A, Hörkkö S, Han KH, Friedman P, Dennis EA and Witztum JL. 1999. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specifc epitopes mediate macrophage recognition. Proc Natl Acad Sci USA 96:6353-6358
13. Clarke MC, Savill J, Jones DB, Noble BS and Brown SB. 2003. Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death. J Cell Biol 160:577-587
14. Dachary-Prigent J, Pasquet JM, Freyssinet JM and Nurden AT. 1995. Calcium involvement in aminophospholipid exposure and microparticle formation during platelet activation: a study using Ca2+-ATPase inhibitors. Biochemistry 34:11625-11634
15. Daleke DL. 2008. Regulation of phospholipid asymmetry in the erythrocyte membrane. Curr Opin Hematol 15:191-195
16. Darland-Ransom M, Wang X, Sun CL, Mapes J, Gengyo-Ando K, Mitani S and Xue D. 2008. Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320:528-531
17. de Botton S, Sabri S, Daugas E, Zermati Y, Guidotti JE, Hermine O, Kroemer G, Vainchenker W and Debili N. 2002. Platelet formation is the consequence of caspase activation within megakaryocytes. Blood 100:1310-1317
18. de Freitas Balanco JM, Moreira ME, Bonomo A, Bozza PT, Amarante-Mendes G, Pirmez C and Barcinski MA. 2001. Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity. Curr Biol 11:1870-1873
19. Dillon SR, Mancini M, Rosen A and Schlissel MS. 2000. Annexin V binds to viable B cells and colocalizes with a marker of lipid rafts upon B cell receptor activation. J Immunol 164:1322-1332
20. Fadeel B and Xue D. 2006. PS externalization: from corpse clearance to drug delivery. Cell Death Dif 13:360-362
21. Fadeel B, Åhlin A, Henter J-I, Orrenius S and Hampton MB. 1998. Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. Blood 92:4808-4818
22. Fadeel B, Gleiss B, Högstrand K, Chandra J, Wiedmer T, Sims PJ, Henter J-I, Orrenius S and Samali A. 1999. Phosphatidylserine exposure during apoptosis is a cell type-specifc event and does not correlate with plasma membrane phospholipid scramblase expression. Biochem Biophys Res Commun 266:504-511
23. Fadeel B, Quinn P, Xue D and Kagan V. 2007. Fat(al) attraction: oxidized lipids act as "eat-me" signals. HFSP J 1:225-229
24. Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL and Henson PM. 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specifc recognition and removal by macrophages. J Immunol 148:2207-2216
25. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY and Henson PM. 1998. Macrophages that have ingested apoptotic cells in vitro inhibit proinfammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890-898
26. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA and Henson PM. 2000. A receptor for phosphatidylserine-specifc clearance of apoptotic cells. Nature 405:85-90
27. Fadok VA, de Cathelineau A, Daleke DL, Henson PM and Bratton DL. 2001. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fbroblasts. J Biol Chem 276:1071-1077
28. Fan X, Krahling S, Smith D, Williamson P and Schlegel RA. 2004. Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes. Mol Biol Cell 15:2863-2872
29. Franc NC, Heitzler P, Ezekowitz RA and White K. 1999. Requirement for croquemort in phagocytosis of apoptotic cells in Drosophila. Science 284:1991-1994
30. Frasch SC, Henson PM, Kailey JM, Richter DA, Janes MS, Fadok VA and Bratton DL. 2000. Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase C8. J Biol Chem 275:23065-23073
31. Frasch SC, Henson PM, Nagaosa K, Fessler MB, Borregaard N and Bratton DL. 2004. Phospholipid fip-fop and phospholipid scramblase 1 (PLSCR1) co-localize to uropod rafts in formylated Met-Leu-Phe-stimulated neutrophils. J Biol Chem 279:17625-17633
32. Freire de Lima CG, Nascimento DO, Soares MB, Bozza PT, Castro-Faria-Neto HC, de Mello FG, DosReis GA and Lopes MF. 2000 Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403:199-203
33. Greenberg ME, Sun M, Zhang R, Febbraio M, Silverstein R and Hazen SL. 2006. Oxidized phosphatidylserine-CD36 interactions play an essential role in macrophage-dependent phagocytosis of apoptotic cells. J Exp Med 203:2613-2625
34. Gurtovenko AA and Vattulainen I. 2007. Lipid transmembrane asymmetry and intrinsic membrane potential: two sides of the same coin. J Am Chem Soc 129:5358-5359
35. Hamon Y, Broccardo C, Chambenoit O, Luciani MF, Toti F, Chaslin S, Freyssinet JM, Devaux PF, McNeish J, Marguet D and Chimini G. 2000. ABC1 promotes engulfment of apoptotic cells and trans-bilayer redistribution of phosphatidylserine. Nat Cell Biol 2:399-406
36. Hampton MB, Vanags DM, Pörn-Ares MI and Orrenius S. 1996. Involvement of extracellular calcium in phosphatidylserine exposure during apoptosis. FEBS Lett 399:277-282 (Pubitemid 26426865)
37. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y and Nagata S. 2004. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-defcient mice. Science 304:1147-1150
38. Hong JR, Lin GH, Lin CJ, Wang WP, Lee CC, Lin TL and Wu JL. 2004. Phosphatidylserine receptor is required for the engulfment of dead apoptotic cells and for normal embryonic development in zebrafsh. Development 131:5417-5427
39. Huang Y, Zhao Q, Zhou CX, Gu ZM, Li D, Xu HZ, Wiedmer T, Sims PJ, Zhao KW and Chen GQ. 2006. Antileukemic roles of human phospholipid scramblase 1 gene, evidence from inducible PLSCR1-expressing leukemic cells. Oncogene 25:6618-6627
40. Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Dufeld JS and Bonventre J V. 2008. Kidney injury molecule-1 is a phos-phatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 118:1657-1668
41. Ikeda M, Kihara A, Denpoh A and Igarashi Y. 2008. Te rim101 pathway is involved in rsb1 expression induced by altered lipid asymmetry. Mol Biol Cell 19:1922-1931
42. Jambrina E, Alonso R, Alcalde M, del Carmen Rodríguez M, Serrano A, Martínez-A C, García-Sancho J and Izquierdo M. 2003. Calcium infux through receptor-operated channel induces mitochondria-triggered paraptotic cell death. J Biol Chem 278:14134-14145
43. Jiang J, Kini V, Belikova N, Serinkan B F, Borisenko GG, Tyurina YY, Tyurin VA and Kagan VE. 2004. Cytochrome c release is required for phosphatidylserine peroxidation during Fas-triggered apop-tosis in lung epithelial A549 cells. Lipids 39:1133-1142
44. Jitkaew S, Witasp E, Zhang S, Kagan VE and Fadeel B. 2009. Induction of caspase-and reactive oxygen species-independent phosphatidyl-serine externalization in primary human neutrophils: role in mac-rophage recognition and engulfment. J Leukoc Biol 85:427-437
45. Kagan VE and Quinn PJ. 2004. Toward oxidative lipidomics of cell signaling. Antioxid Redox Signal 6:199-202
46. Kagan VE, Gleiss B, Tyurina YY, Tyurin VA, Elenström-Magnusson C, Liu SX, Serinkan FB, Arroyo A, Chandra J, Orrenius S and Fadeel B. 2002. A role for oxidative stress in apoptosis: oxidation and externalization of phosphatidylserine is required for macro-phage clearance of cells undergoing Fas-mediated apoptosis. J Immunol 169:487-499 (Pubitemid 34686171)
47. Klomp LW, Bull LN, Knisely AS, van Der Doelen MA, Juijn JA, Berger R, Forget S, Nielsen IM, Eiberg H and Houwen RH. 2000. A missense mutation in FIC1 is associated with greenland familial cholestasis. Hepatology 32:1337-1341
48. Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranof G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyf RH and Freeman GJ. 2007. TIM-1 and TIM-4 glycopro-teins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:927-940
49. Krahling S, Callahan MK, Williamson P and Schlegel RA. 1999. Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages. Cell Death Difer 6:183-189 (Pubitemid 29082307)
50. Krieser RJ, Moore FE, Dresnek D, Pellock BJ, Patel R, Huang A, Brachmann C and White K. 2007. Te Drosophila homolog of the putative phosphatidylserine receptor functions to inhibit apoptosis. Development 134:2407-2414
51. Kuge O and Nishijima M. 2003. Biosynthetic regulation and intrac-ellular transport of phosphatidylserine in mammalian cells. J Biochem 133:397-403
52. Kuijpers TW, Maianski NA, Tool AT, Becker K, Plecko B, Valianpour F, Wanders RJ, Pereira R, Van Hove J, Verhoeven AJ, Roos D, Baas F and Barth PG. 2004. Neutrophils in Barth syndrome (BTHS) avidly bind annexin-V in the absence of apoptosis. Blood 103:3915-3923
53. Kunisaki Y, Masuko S, Noda M, Inayoshi A, Sanui T, Harada M, Sasazuki T and Fukui Y. 2004. Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor. Blood 103:3362-3364
54. Latorre R and Hall JE. 1976. Dipole potential measurements in asymmetric membranes. Nature 264:361-363
55. Lenoir G, Williamson P and Holthuis JC. 2007. On the origin of lipid asymmetry: the fip side of ion transport. Curr Opin Chem Biol 11:654-661
56. Lenoir G, Williamson P, Puts CF and Holthuis JC. 2009. Cdc50p plays a vital role in the ATPase reaction cycle of the putative amino-phospholipid transporter DRS2P. J Biol Chem 284:17956-17967
57. Li MO, Sarkisian MR, Mehal WZ, Rakic P and Flavell RA. 2003. Phosphatidylserine receptor is required for clearance of apop-totic cells. Science 302:1560-1563
58. Li W and Baker NE. 2007. Engulfment is required for cell competition. Cell 129:1215-1225
59. Li W and Tait JF. 1998. Regulatory efect of CD9 on calcium-stimulated phosphatidylserine exposure in Jurkat T lymphocytes. Arch Biochem Biophys 351:89-95
60. Liu J, Dai Q, Chen J, Durrant D, Freeman A, Liu T, Grossman D and Lee RM. 2003. Phospholipid scramblase 3 controls mitochon-drial structure, function, and apoptotic response. Mol Cancer Res 1:892-902
61. Liu J, Epand RF, Durrant D, Grossman D, Chi NW, Epand RM and Lee RM. 2008. Role of phospholipid scramblase 3 in the regulation of tumor necrosis factor-alpha-induced apoptosis. Biochemistry 47:4518-4529
62. Luciani MF and Chimini G. 1996. Te ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J 15:226-235 (Pubitemid 26029202)
63. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM and Green DR. 1995. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpres-sion of Bcl-2 and Abl. J Exp Med 182:1545-1556
64. Martin SJ, Finucane DM, Amarante-Mendes GP, O'Brien GA and Green DR. 1996. Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/ CED-3 protease activity. J Biol Chem 271:28753-28756
65. Martin S, Pombo I, Poncet P, David B, Arock M and Blank U. 2000. Immunologic stimulation of mast cells leads to the reversible exposure of phosphatidylserine in the absence of apoptosis. Int Arch Allergy Immunol 123:249-258
66. Martínez MC and Freyssinet JM. 2001. Deciphering the plasma membrane hallmarks of apoptotic cells: phosphatidylserine transverse redistribution and calcium entry. BMC Cell Biol 2:20
67. Matsura T, Serinkan BF, Jiang J and Kagan VE. 2002. Phosphatidylserine peroxidation/externalization during staurosporine-induced apoptosis in HL-60 cells. FEBS Lett 524:25-30
68. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G and Francone OL. 2000. High density lipoprotein defciency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Nat Acad Sci USA 97:4245-4250
69. Mercer J, Helenius A. 2008. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 320:531-535
70. Miletich JP, Kane WH, Hofmann SL, Stanford N and Majerus PW. 1979. Defciency of factor Xa-factor Va binding sites on the platelets of a patient with a bleeding disorder. Blood 54:1015-1022
71. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T and Nagata S. 2007. Identifcation of Tim4 as a phosphatidylserine receptor. Nature 450:435-439
72. Ndebele K, Gona P, Jin TG, Benhaga N, Chalah A, Degli-Esposti M and Khosravi-Far R. 2008. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced mitochondrial pathway to apoptosis and caspase activation is potentiated by phospholipid scramblase-3. Apoptosis 13:845-856
73. Orrenius S, Zhivotovsky B and Nicotera P. 2003. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552-565
74. Orso E, Broccardo C, Kaminski WE, Böttcher A, Liebisch G, Drobnik W, Götz A, Chambenoit O, Diederich W, Langmann T, Spruss T, Luciani MF, Rothe G, Lackner KJ, Chimini G and Schmitz G. 2000. Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-defcient mice. Nat Genet 24:192-196
75. Park SY, Jung MY, Kim HJ, Lee SJ, Kim SY, Lee BH, Kwon TH, Park RW and Kim IS. 2008. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Difer 15:192-201
76. Park D, Tosello-Trampont AC, Elliott MR, Lu M, Haney LB, Ma Z, Klibanov AL, Mandell JW and Ravichandran KS. 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/ Dock180/Rac module. Nature 450:430-434
77. Pelassy C, Breittmayer JP and Aussel C. 2000. Regulation of phos-phatidylserine exposure at the cell surface by the serine-base exchange enzyme system during CD95-induced apoptosis. Biochem Pharmacol 59:855-863
78. Ricci JE, Muñoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, Schefer IE, Ellisman MH and Green DR. 2004. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117:773-786
79. Rosing J, Bevers EM, Comfurius P, Hemker HC, van Dieijen G, Weiss HJ and Zwaal RF. 1985. Impaired factor X and pro-thrombin activation associated with decreased phospholipid exposure in platelets from a patient with a bleeding disorder. Blood 65:1557-1561
80. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denèfe P and Assmann G. 1999. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352-355
81. Savill J, Dransfeld I, Gregory C and Haslett C. 2002. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965-975
82. Schoenwaelder SM, Yuan Y, Josefsson EC, White MJ, Yao Y, Mason KD, O'Reilly LA, Henley KJ, Ono A, Hsiao S, Willcox A, Roberts AW, Huang DC, Salem HH, Kile BT and Jackson SP. 2009. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 114:663-666
83. Schug ZT and Gottlieb E. 2009. Cardiolipin acts as a mitochondrial signalling platform to launch apoptosis. Biochim Biophys Acta May 18 [Epub ahead of print]
84. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loefer M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM and Kroemer G. 1999. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441-446
85. Tang X, Halleck MS, Schlegel RA and Williamson P. 1996. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 272:1495-1497
86. Toth B, Garabuczi E, Sarang Z, Vereb G, Vámosi G, Aeschlimann D, Blaskó B, Bécsi B, Erdõdi F, Lacy-Hulbert A, Zhang A, Falasca L, Birge RB, Balajthy Z, Melino G, Fésüs L and Szondy Z. 2009. Transglutaminase 2 is needed for the formation of an efcient phagocyte portal in macrophages engulfng apoptotic cells. J Immunol 182:2084-2092
87. Tyurina YY, Serinkan FB, Tyurin VA, Kini V, Yalowich JC, Schroit AJ, Fadeel B and Kagan VE. 2004. Lipid antioxidant, etoposide, inhibits phosphatidylserine externalization and macrophage clearance of apoptotic cells by preventing phosphatidylserine oxidation. J Biol Chem 279:6056-6064
88. Tyurina YY, Basova LV, Konduru NV, Tyurin VA, Potapovich AI, Cai P, Bayir H, Stoyanovsky D, Pitt BR, Shvedova AA, Fadeel B and Kagan VE. 2007. Nitrosative stress inhibits the aminophospholipid translocase resulting in phosphatidyl-serine externalization and macrophage engulfment: implications for the resolution of infammation. J Biol Chem 282:8498-8509
89. Ujhazy P, Ortiz D, Misra S, Li S, Moseley J, Jones H and Arias IM. 2001. Familial intrahepatic cholestasis 1: studies of localization and function. Hepatology 34:768-775
90. Uthaisang W, Nutt LK, Orrenius S, Fadeel B. 2003. Phosphatidylserine exposure in Fas type I cells is mitochondria-dependent. FEBS Lett 545:110-114
91. Vanags DM, Pörn-Ares MI, Coppola S, Burgess DH and Orrenius S. 1996. Protease involvement in fodrin cleavage and phosphati-dylserine exposure in apoptosis. J Biol Chem 271:31075-31085 (Pubitemid 26408546)
92. van den Eijnde SM, van den Hof MJ, Reutelingsperger CP, van Heerde WL, Henfing ME, Vermeij-Keers C, Schutte B, Borgers M and Ramaekers FC. 2001. Transient expression of phosphati-dylserine at cell-cell contact areas is required for myotube formation. J Cell Sci 114:3631-3642
93. van Genderen H, Kenis H, Lux P, Ungeth L, Maassen C, Deckers N, Narula J, Hofstra L and Reutelingsperger C. 2006. In vitro measurement of cell death with the annexin A5 afnity assay. Nat Protoc 1:363-367
94. van Meer G, Voelker DR and Feigenson GW. 2008. Membrane lip-ids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112-124
95. van Raam BJ and Kuijpers TW. 2009. Mitochondrial defects lie at the basis of neutropenia in Barth syndrome. Curr Opin Hematol 16:14-19
96. Venegas V and Zhou Z. 2007. Two alternative mechanisms that regulate the presentation of apoptotic cell engulfment signal in Caenorhabditis elegans. Mol Biol Cell 18:3180-3192
97. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR and Girkontaite I. 1997. Immunosuppressive efects of apoptotic cells. Nature 390:350-351
98. Wanderley JL, Moreira ME, Benjamin A, Bonomo AC and Barcinski MA. 2006. Mimicry of apoptotic cells by exposing phosphatidylserine participates in the establishment of amas-tigotes of Leishmania (L) amazonensis in mammalian hosts. J Immunol 176:1834-1839
99. Wang X, Yang C, Chai J, Shi Y and Xue D. 2002. Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298:1587-1592
100. Wang X, Wu YC, Fadok VA, Lee MC, Gengyo-Ando K, Cheng LC, Ledwich D, Hsu PK, Chen JY, Chou BK, Henson P, Mitani S and Xue D. 2003. Cell corpse engulfment mediated by C. ele-gans phosphatidylserine receptor through CED-5 and CED-12. Science 302:1563-1566
101. Wang X, Wang J, Gengyo-Ando K, Gu L, Sun CL, Yang C, Shi Y, Kobayashi T, Shi Y, Mitani S, Xie XS and Xue D. 2007. C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scram-blase SCRM-1. Nat Cell Biol 9:541-549
102. Weihua Z, Tsan R, Schroit AJ and Fidler IJ. 2005. Apoptotic cells initiate endothelial cell sprouting via electrostatic signaling. Cancer Res 65:11529-11535
103. Weiss HJ, Vicic WJ, Lages BA and Rogers J. 1979. Isolated defciency of platelet procoagulant activity. Am J Med 67:206-213
104. Wiedmer T, Zhou Q, Kwoh DY and Sims PJ. 2000. Identifcation of three new members of the phospholipid scramblase gene family. Biochim Biophys Acta 1467:244-253
105. Wiedmer T, Zhao J, Li L, Zhou Q, Hevener A, Olefsky JM, Curtiss LK and Sims PJ. 2004. Adiposity, dyslipidemia, and insulin resistance in mice with targeted deletion of phospholipid scramblase 3 (PLSCR3). Proc Natl Acad Sci USA 101:13296-13301
106. Williamson P, Christie A, Kohlin T, Schlegel RA, Comfurius P, Harmsma M, Zwaal RF and Bevers EM. 2001. Phospholipid scramblase activation pathways in lymphocytes. Biochemistry 40:8065-8072
107. Williamson P, Halleck MS, Malowitz J, Ng S, Fan X, Krahling S, Remaley AT and Schlegel RA. 2007. Transbilayer phospholipid movements in ABCA1-defcient cells. PLoS ONE 2:e729
108. Witasp E, Kagan V and Fadeel B. 2008. Programmed cell clearance: molecular mechanisms and role in autoimmue disease, chronic infammation, and anti-cancer immune responses. Curr Immunol Rev 4:53-69
109. Wolf C and Quinn PJ. 2008. Lipidomics: practical aspects and applications. Prog Lipid Res 47:15-36
110. Wu YC and Horvitz HR. 1998. Te C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93:951-960
111. Yeung T, Gilbert GE, Shi J, Silvius J, Kapus A and Grinstein S. 2008. Membrane phosphatidylserine regulates surface charge and protein localization. Science 319:210-213
112. Yeung T, Heit B, Dubuisson JF, Fairn GD, Chiu B, Inman R, Kapus A, Swanson M and Grinstein S. 2009. Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol 185:917-928
113. Zhou Q, Zhao J, Stout JG, Luhm RA, Wiedmer T and Sims PJ. 1997. Molecular cloning of human plasma membrane phospholi-pid scramblase. A protein mediating transbilayer movement of plasma membrane phospholipids. J Biol Chem 272:18240-18244
114. Zhou Q, Zhao J, Wiedmer T and Sims PJ. 2002. Normal hemos-tasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1. Blood 99:4030-4038
115. Zhuang J, Ren Y, Snowden RT, Zhu H, Gogvadze V, Savill JS and Cohen GM. 1998. Dissociation of phagocyte recognition of cells undergoing apoptosis from other features of the apoptotic program. J Biol Chem 273:15628-15632
116. Züllig S, Neukomm LJ, Jovanovic M, Charette SJ, Lyssenko NN, Halleck MS, Reutelingsperger CP, Schlegel RA and Hengartner MO. 2007. Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apop-tosis. Curr Biol 17:994-999
117. Zwaal RF and Schroit AJ. 1997. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood 89:1121-1132
118. Zwaal RF, Comfurius P and Bevers EM. 2004. Scott syndrome, a bleeding disorder caused by defective scrambling of membrane phospholipids. Biochim Biophys Acta 1636:119-128
119. Zwaal RF, Comfurius P and Bevers EM. 2005. Surface exposure of phosphatidylserine in pathological cells. Cell Mol Life Sci 62:971-988