Abstract
Programmed cell death is critical to the development of diverse animal species from C. elegans to humans. In C. elegans, the cell death program has three genetically distinguishable phases. During the cell suicide phase, the core cell death machinery is activated through a protein interaction cascade. This activates the caspase CED-3, which promotes numerous pro-apoptotic activities including DNA degradation and exposure of the phosphatidylserine “eat me” signal on the cell corpse surface. Specification of the cell death fate involves transcriptional activation of the cell death initiator EGL-1 or the caspase CED-3 by coordinated actions of specific transcription factors in distinct cell types. In the cell corpse clearance stage, recognition of cell corpses by phagocytes triggers several signaling pathways to induce phagocytosis of apoptotic cell corpses. Cell corpse-enclosing phagosomes ultimately fuse with lysosomes for digestion of phagosomal contents. This article summarizes our current knowledge about programmed cell death and clearance of cell corpses in C. elegans.
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References
Lettre G, Hengartner MO (2006) Developmental apoptosis in C. elegans: a complex CEDnario. Nat Rev Mol Cell Biol 7(2):97–108
Sulston JE, Horvitz HR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1):110–156
Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100(1):64–119
Gumienny TL, Lambie E, Hartwieg E, Horvitz HR, Hengartner MO (1999) Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126(5):1011–1022
Gartner A, Milstein S, Ahmed S, Hodgkin J, Hengartner MO (2000) A conserved checkpoint pathway mediates DNA damage–induced apoptosis and cell cycle arrest in C. elegans. Mol Cell 5(3):435–443
Conradt B, Xue D (2005) Programmed cell death. WormBook: the online review of C. elegans biology, pp 1–13
Horvitz HR (1999) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res 59(7 Suppl):1701s–1706s
Horvitz HR (2003) Nobel lecture. Worms, life and death. Biosci Rep 23(5–6):239–303
Conradt B, Horvitz HR (1998) The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93(4):519–529
Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6):817–829. pii: 0092-8674(86)90004-8
Hengartner MO, Ellis RE, Horvitz HR (1992) Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature 356(6369):494–499
Shaham S, Horvitz HR (1996) Developing Caenorhabditis elegans neurons may contain both cell-death protective and killer activities. Genes Dev 10(5):578–591
Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75(4):641–652
Xue D, Shaham S, Horvitz HR (1996) The Caenorhabditis elegans cell-death protein CED-3 is a cysteine protease with substrate specificities similar to those of the human CPP32 protease. Genes Dev 10(9):1073–1083
Yuan J, Horvitz HR (1992) The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116(2):309–320
Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90(3):405–413
Hengartner MO, Horvitz HR (1994) C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76(4):665–676
Chinnaiyan AM, O’Rourke K, Lane BR, Dixit VM (1997) Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science 275(5303):1122–1126
Wu D, Wallen HD, Nunez G (1997) Interaction and regulation of subcellular localization of CED-4 by CED-9. Science 275(5303):1126–1129
Spector MS, Desnoyers S, Hoeppner DJ, Hengartner MO (1997) Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature 385(6617):653–656. doi:10.1038/385653a0
Parrish J, Metters H, Chen L, Xue D (2000) Demonstration of the in vivo interaction of key cell death regulators by structure-based design of second-site suppressors. Proc Natl Acad Sci USA 97(22):11916–11921
del Peso L, Gonzalez VM, Nunez G (1998) Caenorhabditis elegans EGL-1 disrupts the interaction of CED-9 with CED-4 and promotes CED-3 activation. J Biol Chem 273(50):33495–33500
Chen F, Hersh BM, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, Horvitz HR (2000) Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 287(5457):1485-1489. pii: 8293
Yan N, Chai J, Lee ES, Gu L, Liu Q, He J, Wu JW, Kokel D, Li H, Hao Q, Xue D, Shi Y (2005) Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature 437(7060):831–837
Yan N, Gu L, Kokel D, Chai J, Li W, Han A, Chen L, Xue D, Shi Y (2004) Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell 15(6):999–1006
Qi S, Pang Y, Hu Q, Liu Q, Li H, Zhou Y, He T, Liang Q, Liu Y, Yuan X, Luo G, Li H, Wang J, Yan N, Shi Y (2010) Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4. Cell 141(3):446–457. doi:10.1016/j.cell.2010.03.017
Huang W, Jiang T, Choi W, Qi S, Pang Y, Hu Q, Xu Y, Gong X, Jeffrey PD, Wang J, Shi Y (2013) Mechanistic insights into CED-4-mediated activation of CED-3. Genes Dev 27(18):2039–2048. doi:10.1101/gad.224428.113
Shen Q, Qin F, Gao Z, Cui J, Xiao H, Xu Z, Yang C (2009) Adenine nucleotide translocator cooperates with core cell death machinery to promote apoptosis in Caenorhabditis elegans. Mol Cell Biol 29(14):3881–3893. doi:10.1128/MCB.01509-08
Shaham S, Horvitz HR (1996) An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell 86(2):201–208
Galvin BD, Denning DP, Horvitz HR (2011) SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans. Proc Natl Acad Sci USA 108(5):1998–2003. doi:10.1073/pnas.1018805108
Chiorazzi M, Rui L, Yang Y, Ceribelli M, Tishbi N, Maurer CW, Ranuncolo SM, Zhao H, Xu W, Chan WC, Jaffe ES, Gascoyne RD, Campo E, Rosenwald A, Ott G, Delabie J, Rimsza LM, Shaham S, Staudt LM (2013) Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma. Proc Natl Acad Sci USA 110(10):3943–3948. doi:10.1073/pnas.1217271110
Hirose T, Horvitz HR (2014) The translational regulators GCN-1 and ABCF-3 act together to promote apoptosis in C. elegans. PLoS Genet 10(8):e1004512. doi:10.1371/journal.pgen.1004512
Huang CY, Chen JY, Wu SC, Tan CH, Tzeng RY, Lu PJ, Wu YF, Chen RH, Wu YC (2012) C. elegans EIF-3.K promotes programmed cell death through CED-3 caspase. PLoS One 7(5):e36584. doi:10.1371/journal.pone.0036584
Xue D, Horvitz HR (1997) Caenorhabditis elegans CED-9 protein is a bifunctional cell-death inhibitor. Nature 390(6657):305–308. doi:10.1038/36889
Nakagawa A, Shi Y, Kage-Nakadai E, Mitani S, Xue D (2010) Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease. Science 328(5976):327–334. doi:10.1126/science.1182374
Ge X, Zhao X, Nakagawa A, Gong X, Skeen-Gaar RR, Shi Y, Gong H, Wang X, Xue D (2014) A novel mechanism underlies caspase-dependent conversion of the dicer ribonuclease into a deoxyribonuclease during apoptosis. Cell Res 24(2):218–232. doi:10.1038/cr.2013.160
Chen YZ, Mapes J, Lee ES, Skeen-Gaar RR, Xue D (2013) Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes apoptosis and phosphatidylserine externalization. Nat Commun 4:2726. doi:10.1038/ncomms3726
Breckenridge DG, Kang BH, Kokel D, Mitani S, Staehelin LA, Xue D (2008) Caenorhabditis elegans drp-1 and fis-2 regulate distinct cell-death execution pathways downstream of ced-3 and independent of ced-9. Mol Cell 31(4):586–597. doi:10.1016/j.molcel.2008.07.015
Nakagawa A, Sullivan KD, Xue D (2014) Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway. Nat Struct Mol Biol 21(12):1082–1090. doi:10.1038/nsmb.2915
Shaham S (1998) Identification of multiple Caenorhabditis elegans caspases and their potential roles in proteolytic cascades. J Biol Chem 273(52):35109–35117
Denning DP, Hatch V, Horvitz HR (2013) Both the caspase CSP-1 and a caspase-independent pathway promote programmed cell death in parallel to the canonical pathway for apoptosis in Caenorhabditis elegans. PLoS Genet 9(3):e1003341. doi:10.1371/journal.pgen.1003341
Geng X, Shi Y, Nakagawa A, Yoshina S, Mitani S, Shi Y, Xue D (2008) Inhibition of CED-3 zymogen activation and apoptosis in Caenorhabditis elegans by caspase homolog CSP-3. Nat Struct Mol Biol 15(10):1094–1101. doi:10.1038/nsmb.1488
Geng X, Zhou QH, Kage-Nakadai E, Shi Y, Yan N, Mitani S, Xue D (2009) Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 autoactivation and apoptosis in germ cells. Cell Death Differ 16(10):1385–1394. doi:10.1038/cdd.2009.88
Liu X, Li P, Widlak P, Zou H, Luo X, Garrard WT, Wang X (1998) The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci USA 95(15):8461–8466
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391(6662):43–50. doi:10.1038/34112
Liu X, Zou H, Widlak P, Garrard W, Wang X (1999) Activation of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease). Oligomerization and direct interaction with histone H1. J Biol Chem 274(20):13836–13840
Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391(6662):96–99. doi:10.1038/34214
Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D (2001) Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature 412(6842):90–94
Parrish JZ, Xue D (2003) Functional genomic analysis of apoptotic DNA degradation in C. elegans. Mol Cell 11(4):987–996
Parrish JZ, Yang C, Shen B, Xue D (2003) CRN-1, a Caenorhabditis elegans FEN-1 homologue, cooperates with CPS-6/EndoG to promote apoptotic DNA degradation. EMBO J 22(13):3451–3460
Wang X, Yang C, Chai J, Shi Y, Xue D (2002) Mechanisms of AIF-mediated apoptotic DNA degradation in Caenorhabditis elegans. Science 298(5598):1587–1592
Wu YC, Stanfield GM, Horvitz HR (2000) NUC-1, a Caenorhabditis elegans DNase II homolog, functions in an intermediate step of DNA degradation during apoptosis. Genes Dev 14(5):536–548
Conradt B (2009) Genetic control of programmed cell death during animal development. Annu Rev Genet 43:493–523. doi:10.1146/annurev.genet.42.110807.091533
Peden E, Killian DJ, Xue D (2008) Cell death specification in C. elegans. Cell cycle 7(16):2479–2484
Jiang HS, Wu YC (2014) LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1. PLoS genetics 10(8):e1004513. doi:10.1371/journal.pgen.1004513
Thellmann M, Hatzold J, Conradt B (2003) The Snail-like CES-1 protein of C. elegans can block the expression of the BH3-only cell-death activator gene egl-1 by antagonizing the function of bHLH proteins. Development 130(17):4057–4071
Metzstein MM, Hengartner MO, Tsung N, Ellis RE, Horvitz HR (1996) Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2. Nature 382(6591):545–547. doi:10.1038/382545a0
Metzstein MM, Horvitz HR (1999) The C. elegans cell death specification gene ces-1 encodes a snail family zinc finger protein. Mol Cell 4(3):309–319. pii: S1097-2765(00)80333-0
Hatzold J, Conradt B (2008) Control of apoptosis by asymmetric cell division. PLoS Biol 6(4):e84. doi:10.1371/journal.pbio.0060084
Hirose T, Horvitz HR (2013) An Sp1 transcription factor coordinates caspase-dependent and -independent apoptotic pathways. Nature 500(7462):354–358. doi:10.1038/nature12329
Cordes S, Frank CA, Garriga G (2006) The C. elegans MELK ortholog PIG-1 regulates cell size asymmetry and daughter cell fate in asymmetric neuroblast divisions. Development 133(14):2747–2756. doi:10.1242/dev.02447
Gurling M, Talavera K, Garriga G (2014) The DEP domain-containing protein TOE-2 promotes apoptosis in the Q lineage of C. elegans through two distinct mechanisms. Development 141(13):2724–2734. doi:10.1242/dev.110486
Teuliere J, Cordes S, Singhvi A, Talavera K, Garriga G (2014) Asymmetric neuroblast divisions producing apoptotic cells require the cytohesin GRP-1 in Caenorhabditis elegans. Genetics 198(1):229–247. doi:10.1534/genetics.114.167189
Singhvi A, Teuliere J, Talavera K, Cordes S, Ou G, Vale RD, Prasad BC, Clark SG, Garriga G (2011) The Arf GAP CNT-2 regulates the apoptotic fate in C. elegans asymmetric neuroblast divisions. Curr Biol 21(11):948–954. doi:10.1016/j.cub.2011.04.025
Conradt B, Horvitz HR (1999) The TRA-1A sex determination protein of C. elegans regulates sexually dimorphic cell deaths by repressing the egl-1 cell death activator gene. Cell 98(3):317–327
Starostina NG, Lim JM, Schvarzstein M, Wells L, Spence AM, Kipreos ET (2007) A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination. Dev Cell 13(1):127–139. doi:10.1016/j.devcel.2007.05.008
Zarkower D (2006) Somatic sex determination. WormBook: the online review of C. elegans biology, pp 1–12. doi:10.1895/wormbook.1.84.1
Jager S, Schwartz HT, Horvitz HR, Conradt B (2004) The Caenorhabditis elegans F-box protein SEL-10 promotes female development and may target FEM-1 and FEM-3 for degradation by the proteasome. Proc Natl Acad Sci USA 101(34):12549–12554. doi:10.1073/pnas.0405087101
Peden E, Kimberly E, Gengyo-Ando K, Mitani S, Xue D (2007) Control of sex-specific apoptosis in C. elegans by the BarH homeodomain protein CEH-30 and the transcriptional repressor UNC-37/Groucho. Genes Dev 21(23):3195–3207. doi:10.1101/gad.1607807
Schwartz HT, Horvitz HR (2007) The C. elegans protein CEH-30 protects male-specific neurons from apoptosis independently of the Bcl-2 homolog CED-9. Genes Dev 21(23):3181–3194. doi:10.1101/gad.1607007
Liu H, Strauss TJ, Potts MB, Cameron S (2006) Direct regulation of egl-1 and of programmed cell death by the Hox protein MAB-5 and by CEH-20, a C. elegans homolog of Pbx1. Development 133(4):641–650. doi:10.1242/dev.02234
Wang J, Chitturi J, Ge Q, Laskova V, Wang W, Li X, Ding M, Zhen M, Huang X (2015) The C. elegans COE transcription factor UNC-3 activates lineage-specific apoptosis and affects neurite growth in the RID lineage. Development 142(8):1447–1457. doi:10.1242/dev.119479
Hirose T, Galvin BD, Horvitz HR (2010) Six and Eya promote apoptosis through direct transcriptional activation of the proapoptotic BH3-only gene egl-1 in Caenorhabditis elegans. Proc Natl Acad Sci USA 107(35):15479–15484. doi:10.1073/pnas.1010023107
Maurer CW, Chiorazzi M, Shaham S (2007) Timing of the onset of a developmental cell death is controlled by transcriptional induction of the C. elegans ced-3 caspase-encoding gene. Development 134(7):1357–1368. doi:10.1242/dev.02818
Kritikou EA, Milstein S, Vidalain PO, Lettre G, Bogan E, Doukoumetzidis K, Gray P, Chappell TG, Vidal M, Hengartner MO (2006) C. elegans GLA-3 is a novel component of the MAP kinase MPK-1 signaling pathway required for germ cell survival. Genes Dev 20(16):2279–2292
Lettre G, Kritikou EA, Jaeggi M, Calixto A, Fraser AG, Kamath RS, Ahringer J, Hengartner MO (2004) Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans. Cell Death Differ 11(11):1198–1203
Schertel C, Conradt B (2007) C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions. Development 134(20):3691–3701. doi:10.1242/dev.004606
Park D, Jia H, Rajakumar V, Chamberlin HM (2006) Pax2/5/8 proteins promote cell survival in C. elegans. Development 133(21):4193–4202. doi:10.1242/dev.02614
Derry WB, Putzke AP, Rothman JH (2001) Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294(5542):591–595
Schumacher B, Hofmann K, Boulton S, Gartner A (2001) The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr Biol 11(21):1722–1727
Schumacher B, Schertel C, Wittenburg N, Tuck S, Mitani S, Gartner A, Conradt B, Shaham S (2005) C. elegans ced-13 can promote apoptosis and is induced in response to DNA damage. Cell Death Differ 12(2):153–161
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288(5468):1053–1058
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B (2001) PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell 7(3):673–682
Gartner A, Boag PR, Blackwell TK (2008) Germline survival and apoptosis. WormBook: the online review of C. elegans biology, pp 1–20
Schumacher B, Hanazawa M, Lee MH, Nayak S, Volkmann K, Hofmann ER, Hengartner M, Schedl T, Gartner A (2005) Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis. Cell 120(3):357–368
Yang M, Sun J, Sun X, Shen Q, Gao Z, Yang C (2009) Caenorhabditis elegans protein arginine methyltransferase PRMT-5 negatively regulates DNA damage-induced apoptosis. PLoS Genet 5(6):e1000514
Greiss S, Hall J, Ahmed S, Gartner A (2008) C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway parallel to cep-1/p53 during DNA damage-induced apoptosis. Genes Dev 22(20):2831–2842. doi:10.1101/gad.482608
Xu J, Sun X, Jing Y, Wang M, Liu K, Jian Y, Yang M, Cheng Z, Yang C (2012) MRG-1 is required for genomic integrity in Caenorhabditis elegans germ cells. Cell Res 22(5):886–902. doi:10.1038/cr.2012.2
Bhalla N, Dernburg AF (2005) A conserved checkpoint monitors meiotic chromosome synapsis in Caenorhabditis elegans. Science 310(5754):1683–1686
Dombecki CR, Chiang AC, Kang HJ, Bilgir C, Stefanski NA, Neva BJ, Klerkx EP, Nabeshima K (2011) The chromodomain protein MRG-1 facilitates SC-independent homologous pairing during meiosis in Caenorhabditis elegans. Dev Cell 21(6):1092–1103. doi:10.1016/j.devcel.2011.09.019
Mei F, Chen PF, Dombecki CR, Aljabban I, Nabeshima K (2015) A defective meiotic outcome of a failure in homologous pairing and synapsis is masked by meiotic quality control. PLoS One 10(8):e0134871. doi:10.1371/journal.pone.0134871
Denning DP, Hatch V, Horvitz HR (2012) Programmed elimination of cells by caspase-independent cell extrusion in C. elegans. Nature 488 (7410):226-230. doi:10.1038/nature11240
Rosenblatt J (2012) Programmed cell death: a new way worms get rid of unwanted cells. Curr Biol 22(19):R844–R846. doi:10.1016/j.cub.2012.08.013
Abraham MC, Lu Y, Shaham S (2007) A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans. Dev Cell 12(1):73–86. doi:10.1016/j.devcel.2006.11.012
Blum ES, Abraham MC, Yoshimura S, Lu Y, Shaham S (2012) Control of nonapoptotic developmental cell death in Caenorhabditis elegans by a polyglutamine-repeat protein. Science 335(6071):970–973. doi:10.1126/science.1215156
Vlachos M, Tavernarakis N (2010) Non-apoptotic cell death in Caenorhabditis elegans. Dev Dyn 239(5):1337–1351. doi:10.1002/dvdy.22230
Reddien PW, Cameron S, Horvitz HR (2001) Phagocytosis promotes programmed cell death in C. elegans. Nature 412(6843):198–202. doi:10.1038/35084096
Hoeppner DJ, Hengartner MO, Schnabel R (2001) Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412(6843):202–206
Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148(7):2207–2216
Wang X, Wang J, Gengyo-Ando K, Gu L, Sun CL, Yang C, Shi Y, Kobayashi T, Shi Y, Mitani S, Xie XS, Xue D (2007) C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1. Nat Cell Biol 9(5):541–549
Darland-Ransom M, Wang X, Sun CL, Mapes J, Gengyo-Ando K, Mitani S, Xue D (2008) Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320(5875):528–531
Zullig S, Neukomm LJ, Jovanovic M, Charette SJ, Lyssenko NN, Halleck MS, Reutelingsperger CP, Schlegel RA, Hengartner MO (2007) Aminophospholipid translocase TAT-1 promotes phosphatidylserine exposure during C. elegans apoptosis. Curr Biol 17(11):994–999
Venegas V, Zhou Z (2007) Two alternative mechanisms that regulate the presentation of apoptotic cell engulfment signal in Caenorhabditis elegans. Mol Biol Cell 18(8):3180–3192. doi:10.1091/mbc.E07-02-0138
Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341(6144):403–406. doi:10.1126/science.1236758
Li Z, Venegas V, Nagaoka Y, Morino E, Raghavan P, Audhya A, Nakanishi Y, Zhou Z (2015) Necrotic cells actively attract phagocytes through the collaborative action of two distinct PS-exposure mechanisms. PLoS Genet 11(6):e1005285. doi:10.1371/journal.pgen.1005285
Zhou Z, Hartwieg E, Horvitz HR (2001) CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104(1):43–56. pii :S0092-8674(01)00190-8
Wang X, Li W, Zhao D, Liu B, Shi Y, Chen B, Yang H, Guo P, Geng X, Shang Z, Peden E, Kage-Nakadai E, Mitani S, Xue D (2010) Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor. Nat Cell Biol 12(7):655–664
Kang Y, Zhao D, Liang H, Liu B, Zhang Y, Liu Q, Wang X, Liu Y (2012) Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment. Genes Dev 26(12):1339–1350. doi:10.1101/gad.187815.112
Wu YC, Horvitz HR (1998) The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93(6):951–960. pii: S0092-8674(00)81201-5
Callahan MK, Williamson P, Schlegel RA (2000) Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes. Cell Death Differ 7(7):645–653. doi:10.1038/sj.cdd.4400690
Callahan MK, Halleck MS, Krahling S, Henderson AJ, Williamson P, Schlegel RA (2003) Phosphatidylserine expression and phagocytosis of apoptotic thymocytes during differentiation of monocytic cells. J Leukoc Biol 74(5):846–856. doi:10.1189/jlb.0902433
Marguet D, Luciani MF, Moynault A, Williamson P, Chimini G (1999) Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nat Cell Biol 1(7):454–456. doi:10.1038/15690
Zhang Y, Wang H, Kage-Nakadai E, Mitani S, Wang X (2012) C. elegans secreted lipid-binding protein NRF-5 mediates PS appearance on phagocytes for cell corpse engulfment. Curr Biol 22(14):1276–1284. doi:10.1016/j.cub.2012.06.004
Mapes J, Chen YZ, Kim A, Mitani S, Kang BH, Xue D (2012) CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells. Curr Biol 22(14):1267–1275. doi:10.1016/j.cub.2012.05.052
Yang H, Chen YZ, Zhang Y, Wang X, Zhao X, Godfroy JI 3rd, Liang Q, Zhang M, Zhang T, Yuan Q, Ann Royal M, Driscoll M, Xia NS, Yin H, Xue D (2015) A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nat Commun 6:5717. doi:10.1038/ncomms6717
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, Xue D (2003) Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12. Science 302(5650):1563–1566
Neumann B, Coakley S, Giordano-Santini R, Linton C, Lee ES, Nakagawa A, Xue D, Hilliard MA (2015) EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517(7533):219–222. doi:10.1038/nature14102
Hsu TY, Wu YC (2010) Engulfment of apoptotic cells in C. elegans is mediated by integrin alpha/SRC signaling. Curr Biol 20(6):477–486. doi:10.1016/j.cub.2010.01.062
Hsieh HH, Hsu TY, Jiang HS, Wu YC (2012) Integrin alpha PAT-2/CDC-42 signaling is required for muscle-mediated clearance of apoptotic cells in Caenorhabditis elegans. PLoS Genet 8(5):e1002663. doi:10.1371/journal.pgen.1002663
Cabello J, Neukomm LJ, Gunesdogan U, Burkart K, Charette SJ, Lochnit G, Hengartner MO, Schnabel R (2010) The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac. PLoS Biol 8(2):e1000297. doi:10.1371/journal.pbio.1000297
Gumienny TL, Brugnera E, Tosello-Trampont AC, Kinchen JM, Haney LB, Nishiwaki K, Walk SF, Nemergut ME, Macara IG, Francis R, Schedl T, Qin Y, Van Aelst L, Hengartner MO, Ravichandran KS (2001) CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107(1):27–41
Wu YC, Tsai MC, Cheng LC, Chou CJ, Weng NY (2001) C. elegans CED-12 acts in the conserved crkII/DOCK180/Rac pathway to control cell migration and cell corpse engulfment. Dev Cell 1(4):491–502
Zhou Z, Caron E, Hartwieg E, Hall A, Horvitz HR (2001) The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev Cell 1(4):477–489
Wu YC, Horvitz HR (1998) C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392(6675):501–504. doi:10.1038/33163
Reddien PW, Horvitz HR (2000) CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol 2(3):131–136
deBakker CD, Haney LB, Kinchen JM, Grimsley C, Lu M, Klingele D, Hsu PK, Chou BK, Cheng LC, Blangy A, Sondek J, Hengartner MO, Wu YC, Ravichandran KS (2004) Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Curr Biol 14(24):2208–2216
Liu QA, Hengartner MO (1998) Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93(6):961–972
Su HP, Nakada-Tsukui K, Tosello-Trampont AC, Li Y, Bu G, Henson PM, Ravichandran KS (2002) Interaction of CED-6/GULP, an adapter protein involved in engulfment of apoptotic cells with CED-1 and CD91/low density lipoprotein receptor-related protein (LRP). J Biol Chem 277(14):11772–11779
Yu X, Odera S, Chuang CH, Lu N, Zhou Z (2006) C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells. Dev Cell 10(6):743–757
Chen D, Jian Y, Liu X, Zhang Y, Liang J, Qi X, Du H, Zou W, Chen L, Chai Y, Ou G, Miao L, Wang Y, Yang C (2013) Clathrin and AP2 are required for phagocytic receptor-mediated apoptotic cell clearance in Caenorhabditis elegans. PLoS Genet 9(5):e1003517. doi:10.1371/journal.pgen.1003517
Shen Q, He B, Lu N, Conradt B, Grant BD, Zhou Z (2013) Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans. Development 140(15):3230–3243. doi:10.1242/dev.093732
Kinchen JM, Cabello J, Klingele D, Wong K, Feichtinger R, Schnabel H, Schnabel R, Hengartner MO (2005) Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans. Nature 434(7029):93–99
Neukomm LJ, Zeng S, Frei AP, Huegli PA, Hengartner MO (2014) Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans. Cell Death Differ 21(6):845–853. doi:10.1038/cdd.2014.23
Zou W, Lu Q, Zhao D, Li W, Mapes J, Xie Y, Wang X (2009) Caenorhabditis elegans myotubularin MTM-1 negatively regulates the engulfment of apoptotic cells. PLoS Genet 5(10):e1000679
Neukomm LJ, Nicot AS, Kinchen JM, Almendinger J, Pinto SM, Zeng S, Doukoumetzidis K, Tronchere H, Payrastre B, Laporte JF, Hengartner MO (2011) The phosphoinositide phosphatase MTM-1 regulates apoptotic cell corpse clearance through CED-5–CED-12 in C. elegans. Development 138(10):2003–2014. doi:10.1242/dev.060012
Neukomm LJ, Frei AP, Cabello J, Kinchen JM, Zaidel-Bar R, Ma Z, Haney LB, Hardin J, Ravichandran KS, Moreno S, Hengartner MO (2011) Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans. Nat Cell Biol 13(1):79–86. doi:10.1038/ncb2138
Hurwitz ME, Vanderzalm PJ, Bloom L, Goldman J, Garriga G, Horvitz HR (2009) Abl kinase inhibits the engulfment of apopotic cells in Caenorhabditis elegans. PLoS Biol 7(4):e99
Bohdanowicz M, Grinstein S (2013) Role of phospholipids in endocytosis, phagocytosis, and macropinocytosis. Physiol Rev 93(1):69–106. doi:10.1152/physrev.00002.2012
Flannagan RS, Jaumouille V, Grinstein S (2012) The cell biology of phagocytosis. Annu Rev Pathol 7:61–98. doi:10.1146/annurev-pathol-011811-132445
Cheng S, Wang K, Zou W, Miao R, Huang Y, Wang H, Wang X (2015) PtdIns(4,5)P2 and PtdIns3P coordinate to regulate phagosomal sealing for apoptotic cell clearance. J Cell Biol 210(3):485–502. doi:10.1083/jcb.201501038
Almendinger J, Doukoumetzidis K, Kinchen JM, Kaech A, Ravichandran KS, Hengartner MO (2011) A conserved role for SNX9-family members in the regulation of phagosome maturation during engulfment of apoptotic cells. PLoS One 6(4):e18325. doi:10.1371/journal.pone.0018325
Lu N, Shen Q, Mahoney TR, Liu X, Zhou Z (2010) Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling. Mol Biol Cell 22(3):354–374. doi:10.1091/mbc.E10-09-0756
Lundmark R, Carlsson SR (2009) SNX9—a prelude to vesicle release. J Cell Sci 122(Pt 1):5–11. doi:10.1242/jcs.037135
Bohdanowicz M, Balkin DM, De Camilli P, Grinstein S (2011) Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling. Mol Biol Cell 23(1):176–187. doi:10.1091/mbc.E11-06-0489
Lu N, Shen Q, Mahoney TR, Neukomm LJ, Wang Y, Zhou Z (2012) Two PI 3-kinases and one PI 3-phosphatase together establish the cyclic waves of phagosomal PtdIns(3)P critical for the degradation of apoptotic cells. PLoS Biol 10(1):e1001245. doi:10.1371/journal.pbio.1001245
Cheng S, Wu Y, Lu Q, Yan J, Zhang H, Wang X (2013) Autophagy genes coordinate with the class II PI/PtdIns 3-kinase PIKI-1 to regulate apoptotic cell clearance in C. elegans. Autophagy 9(12):2022–2032. doi:10.4161/auto.26323
Huang S, Jia K, Wang Y, Zhou Z, Levine B (2012) Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development. Autophagy 9(2). pii: 22352
Chen D, Xiao H, Zhang K, Wang B, Gao Z, Jian Y, Qi X, Sun J, Miao L, Yang C (2010) Retromer is required for apoptotic cell clearance by phagocytic receptor recycling. Science 327(5970):1261–1264. doi:10.1126/science.1184840
Kinchen JM, Doukoumetzidis K, Almendinger J, Stergiou L, Tosello-Trampont A, Sifri CD, Hengartner MO, Ravichandran KS (2008) A pathway for phagosome maturation during engulfment of apoptotic cells. Nat Cell Biol 10(5):556–566
Li W, Zou W, Zhao D, Yan J, Zhu Z, Lu J, Wang X (2009) C. elegans Rab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5. Development 136(14):2445–2455
Kinchen JM, Ravichandran KS (2010) Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature 464(7289):778–782
Nieto C, Almendinger J, Gysi S, Gomez-Orte E, Kaech A, Hengartner MO, Schnabel R, Moreno S, Cabello J (2010) ccz-1 mediates the digestion of apoptotic corpses in C. elegans. J Cell Sci 123(Pt 12):2001–2007. doi:10.1242/jcs.062331
Yu X, Lu N, Zhou Z (2008) Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells. PLoS Biol 6(3):e61
Xiao H, Chen D, Fang Z, Xu J, Sun X, Song S, Liu J, Yang C (2009) Lysosome biogenesis mediated by vps-18 affects apoptotic cell degradation in Caenorhabditis elegans. Mol Biol Cell 20(1):21–32. doi:10.1091/mbc.E08-04-0441
Sasaki A, Nakae I, Nagasawa M, Hashimoto K, Abe F, Saito K, Fukuyama M, Gengyo-Ando K, Mitani S, Katada T, Kontani K (2013) Arl8/ARL-8 functions in apoptotic cell removal by mediating phagolysosome formation in Caenorhabditis elegans. Mol Biol Cell 24(10):1584–1592. doi:10.1091/mbc.E12-08-0628
Mangahas PM, Yu X, Miller KG, Zhou Z (2008) The small GTPase Rab2 functions in the removal of apoptotic cells in Caenorhabditis elegans. J Cell Biol 180(2):357–373
Lu Q, Zhang Y, Hu T, Guo P, Li W, Wang X (2008) C. elegans Rab GTPase 2 is required for the degradation of apoptotic cells. Development 135(6):1069–1080. doi:10.1242/dev.016063
Guo P, Hu T, Zhang J, Jiang S, Wang X (2010) Sequential action of Caenorhabditis elegans Rab GTPases regulates phagolysosome formation during apoptotic cell degradation. Proc Natl Acad Sci USA 107(42):18016–18021
Xu M, Liu Y, Zhao L, Gan Q, Wang X, Yang C (2014) The lysosomal cathepsin protease CPL-1 plays a leading role in phagosomal degradation of apoptotic cells in Caenorhabditis elegans. Mol Biol Cell 25(13):2071–2083. doi:10.1091/mbc.E14-01-0015
Huang J, Wang H, Chen Y, Wang X, Zhang H (2012) Residual body removal during spermatogenesis in C. elegans requires genes that mediate cell corpse clearance. Development 139(24):4613–4622. doi:10.1242/dev.086769
Chai Y, Tian D, Yang Y, Feng G, Cheng Z, Li W, Ou G (2012) Apoptotic regulators promote cytokinetic midbody degradation in C. elegans. J Cell Biol 199(7):1047–1055. doi:10.1083/jcb.201209050
Acknowledgments
We apologize to colleagues whose work could not be mentioned owing to space constraint. We thank Shiya Cheng, Qiwen Gan, and Mengli Shi for assistance in figure preparation and Dr. Isabel Hanson for editing services. Research in the authors’ laboratories was supported by the National Natural Science Foundation of China (31325015 to X.W., 31025015 and 31230043 to C.Y.), the National Basic Research Program of China (2010CB835202, 2013CB910101, and 2014CB849700 to X.W., 2013CB910102 and 2011CB910102 to C.Y.), the Chinese Academy of Sciences (KJZD-EW-L08 to C.Y.), and an International Early Career Scientist grant from the Howard Hughes Medical Institute to X.W.
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Wang, X., Yang, C. Programmed cell death and clearance of cell corpses in Caenorhabditis elegans . Cell. Mol. Life Sci. 73, 2221–2236 (2016). https://doi.org/10.1007/s00018-016-2196-z
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DOI: https://doi.org/10.1007/s00018-016-2196-z