title: Constitutive exposure of phosphatidylserine on viable cells.
abstract: Apoptotic cells are quickly recognized and engulfed by phagocytes to prevent the release of noxious materials from dying cells. Phosphatidylserine (PS) exposed on the surface of apoptotic cells is a proposed "eat-me" signal for the phagocytes. Transmembrane protein 16F (TMEM16F), a membrane protein with eight transmembrane segments, has the Ca-dependent phospholipid scramblase activity. Here we show that when lymphoma cells were transformed with a constitutively active form of TMEM16F, they exposed a high level of PS that was comparable to that observed on apoptotic cells. The PS-exposing cells were morphologically normal and grew normally. They efficiently responded to interleukin 3 and underwent apoptosis upon treatment with Fas ligand. The viable PS-exposing cells bound to peritoneal macrophages at 4 °C, but not at 25 °C. Accordingly, these cells were not engulfed by macrophages. When apoptotic cells were injected i.v. into mice, they were phagocytosed by CD11c(+)CD8(+) dendritic cells (DCs) in the spleen, but the PS-exposing living cells were not phagocytosed by these DCs. Furthermore, when PS-exposing lymphoma cells were transplanted s.c. into nude mice, they generated tumors as efficiently as parental lymphoma cells that did not expose PS. These results indicated that PS exposure alone is not sufficient to be recognized by macrophages as an eat-me signal.
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine,  Kyoto University, Kyoto 606-8501,  Japan.
authors.forename: Katsumori
authors.initials: K
authors.lastname: Segawa
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000075368:Anoctamins; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003713:Dendritic Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010587:Phagocytosis / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism*; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*
chemical_list: C555078:ANO6 protein, human; D000075368:Anoctamins; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins
references.citation: EMBO J. 1995 Mar 15;14(6):1129-35
references.pmid: 7536672
references.citation: J Biol Chem. 2007 Apr 6;282(14):10487-97
references.pmid: 17284440
references.citation: J Exp Med. 2004 Aug 16;200(4):459-67
references.pmid: 15302904
references.citation: J Immunol. 2000 Feb 1;164(3):1322-32
references.pmid: 10640746
references.citation: Biochim Biophys Acta. 1992 Feb 3;1133(3):275-85
references.pmid: 1737061
references.citation: J Biol Chem. 2001 Jan 12;276(2):1071-7
references.pmid: 10986279
references.citation: Am J Pathol. 1984 Jun;115(3):426-36
references.pmid: 6610362
references.citation: Prog Lipid Res. 2003 Sep;42(5):423-38
references.pmid: 12814644
references.citation: Blood. 2006 Dec 15;108(13):4094-101
references.pmid: 16912227
references.citation: Cell Death Differ. 2003 Mar;10(3):371-82
references.pmid: 12700637
references.citation: Cell. 1997 Feb 7;88(3):355-65
references.pmid: 9039262
references.citation: Biochem Biophys Res Commun. 2004 Sep 10;322(1):197-202
references.pmid: 15313191
references.citation: J Exp Med. 2002 May 20;195(10):1289-302
references.pmid: 12021309
references.citation: J Exp Med. 2010 Aug 30;207(9):1807-17
references.pmid: 20805564
references.citation: Nature. 2002 May 9;417(6885):182-7
references.pmid: 12000961
references.citation: Cell. 1997 Feb 7;88(3):347-54
references.pmid: 9039261
references.citation: Annu Rev Physiol. 2003;65:701-34
references.pmid: 12471163
references.citation: J Clin Invest. 2007 Aug;117(8):2268-78
references.pmid: 17657313
references.citation: J Biol Chem. 2004 Feb 13;279(7):6056-64
references.pmid: 14630936
references.citation: J Biol Chem. 2001 Jun 8;276(23):20589-96
references.pmid: 11279185
references.citation: Science. 2000 Jun 16;288(5473):2051-4
references.pmid: 10856220
references.citation: J Immunol. 2003 Dec 1;171(11):5718-26
references.pmid: 14634079
references.citation: J Biol Chem. 1990 Aug 15;265(23):14008-15
references.pmid: 1696260
references.citation: Cell Death Differ. 1999 Feb;6(2):183-9
references.pmid: 10200565
references.citation: Nature. 2010 Dec 9;468(7325):834-8
references.pmid: 21107324
references.citation: J Leukoc Biol. 2008 Aug;84(2):499-509
references.pmid: 18511572
references.citation: Micron. 2006;37(6):509-17
references.pmid: 16497505
references.citation: Nature. 2002 Jul 11;418(6894):200-3
references.pmid: 12110892
references.citation: Biochem Biophys Res Commun. 2009 Sep 11;387(1):58-63
references.pmid: 19559673
references.citation: Thromb Res. 1992 Sep 1;67(5):517-31
references.pmid: 1448786
references.citation: Cell. 2010 Mar 5;140(5):619-30
references.pmid: 20211132
references.citation: Cell Death Differ. 2004 Aug;11(8):943-5
references.pmid: 15031725
references.citation: Nature. 2007 Nov 15;450(7168):435-9
references.pmid: 17960135
references.citation: Mol Biol Cell. 2006 Jul;17(7):3197-210
references.pmid: 16672382
references.citation: Cell. 2005 Oct 21;123(2):321-34
references.pmid: 16239148
references.citation: J Biol Chem. 2003 Oct 17;278(42):41282-93
references.pmid: 12853445
references.citation: Nature. 1998 Jan 1;391(6662):96-9
references.pmid: 9422513
references.citation: J Cell Sci. 2001 Oct;114(Pt 20):3631-42
references.pmid: 11707515
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11784-9
references.pmid: 18689689
references.citation: Arch Biochem Biophys. 2003 May 1;413(1):41-52
references.pmid: 12706340
references.citation: Exp Hematol. 2003 Nov;31(11):1007-14
references.pmid: 14585362
references.citation: Cell Death Differ. 2008 Feb;15(2):243-50
references.pmid: 17571081