Gene Symbol: ced-4
Description: Cell death protein 4
Alias: Cell death protein 4
Species: Caenorhabditis elegans

Top Publications

  1. Chinnaiyan A, O Rourke K, Lane B, Dixit V. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science. 1997;275:1122-6 pubmed
    ..Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases. ..
  2. Dasgupta N, Patel A, Scott B, Crowder C. Hypoxic preconditioning requires the apoptosis protein CED-4 in C. elegans. Curr Biol. 2007;17:1954-9 pubmed
    ..CED-4/Apaf-1 is essential for HP in C. elegans and acts through a mechanism independent of the classical apoptosis pathway. ..
  3. Shaham S, Horvitz H. An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell. 1996;86:201-8 pubmed
    ..We propose that a balance between opposing ced-4 functions influences the decision of a cell to live or to die by programmed cell death and that both ced-9 and ced-4 protective functions are required to prevent programmed cell death. ..
  4. Wu D, Wallen H, Nunez G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science. 1997;275:1126-9 pubmed
    ..Thus, the actions of CED-4 and CED-9 are directly linked, which could provide the basis for the regulation of programmed cell death in C. elegans. ..
  5. Geng X, Zhou Q, Kage Nakadai E, Shi Y, Yan N, Mitani S, et al. Caenorhabditis elegans caspase homolog CSP-2 inhibits CED-3 autoactivation and apoptosis in germ cells. Cell Death Differ. 2009;16:1385-94 pubmed publisher
    ..elegans caspase homologs use the same mechanism to prevent caspase autoactivation and apoptosis in different tissues, suggesting that this could be a generally applicable strategy for regulating caspase activation and apoptosis. ..
  6. Yan N, Xu Y, Shi Y. 2:1 Stoichiometry of the CED-4-CED-9 complex and the tetrameric CED-4: insights into the regulation of CED-3 activation. Cell Cycle. 2006;5:31-4 pubmed
    ..On the basis of structural and biochemical analyses, working models are proposed to explain the mechanism by which CED-4 facilitates CED-3 activation. ..
  7. Pinan Lucarré B, Gabel C, Reina C, Hulme S, Shevkoplyas S, Slone R, et al. The core apoptotic executioner proteins CED-3 and CED-4 promote initiation of neuronal regeneration in Caenorhabditis elegans. PLoS Biol. 2012;10:e1001331 pubmed publisher
    ..This study documents reconstructive roles for proteins known to orchestrate apoptotic death and links previously unconnected observations in the vertebrate literature to suggest a similar pathway may be conserved in higher organisms. ..
  8. Pourkarimi E, Greiss S, Gartner A. Evidence that CED-9/Bcl2 and CED-4/Apaf-1 localization is not consistent with the current model for C. elegans apoptosis induction. Cell Death Differ. 2012;19:406-15 pubmed publisher
    ..Our results suggest that the cell death protection conferred by CED-9 cannot be solely explained by a direct interaction with CED-4. ..
  9. Qi S, Pang Y, Hu Q, Liu Q, Li H, Zhou Y, et al. Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4. Cell. 2010;141:446-57 pubmed publisher
    ..The structure of the CED-4 apoptosome reveals shared principles for the NB-ARC family of AAA(+) ATPases and suggests a mechanism for the activation of CED-3. ..

More Information


  1. Zermati Y, Mouhamad S, Stergiou L, Besse B, Galluzzi L, Boehrer S, et al. Nonapoptotic role for Apaf-1 in the DNA damage checkpoint. Mol Cell. 2007;28:624-37 pubmed
    ..Hence, Apaf-1 exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage. These data point to a role for Apaf-1 as a bona fide tumor suppressor. ..
  2. Yan N, Chai J, Lee E, Gu L, Liu Q, He J, et al. Structure of the CED-4-CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans. Nature. 2005;437:831-7 pubmed
    ..The released CED-4 dimer further dimerizes to form a tetramer, which facilitates the autoactivation of CED-3. Together, our studies provide important insights into the regulation of cell death activation in C. elegans. ..
  3. Chan S, Yee K, Tan K, Yu V. The Caenorhabditis elegans sex determination protein FEM-1 is a CED-3 substrate that associates with CED-4 and mediates apoptosis in mammalian cells. J Biol Chem. 2000;275:17925-8 pubmed
    ..Similarly, Apaf-1, the mammalian homologue of CED-4 was found to associate with F1Aalpha. These data suggest that FEM-1 and F1Aalpha may mediate apoptosis by communicating directly with the core machinery of apoptosis. ..
  4. Chen F, Hersh B, Conradt B, Zhou Z, Riemer D, Gruenbaum Y, et al. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science. 2000;287:1485-9 pubmed
    ..Thus, a change in the subcellular localization of CED-4 may drive programmed cell death. ..
  5. del Peso L, Gonzalez V, Inohara N, Ellis R, Nunez G. Disruption of the CED-9.CED-4 complex by EGL-1 is a critical step for programmed cell death in Caenorhabditis elegans. J Biol Chem. 2000;275:27205-11 pubmed
    ..CED-4 complex. These studies suggest that the release of CED-4 from the CED-9.CED-4 complex is a necessary step for induction of programmed cell death in C. elegans. ..
  6. Denning D, Hatch V, Horvitz H. Programmed elimination of cells by caspase-independent cell extrusion in C. elegans. Nature. 2012;488:226-30 pubmed publisher
    ..Our findings reveal a mechanism for apoptotic cell elimination that is fundamentally distinct from that of canonical programmed cell death. ..
  7. Chen L, McCloskey T, Joshi P, Rothman J. ced-4 and proto-oncogene tfg-1 antagonistically regulate cell size and apoptosis in C. elegans. Curr Biol. 2008;18:1025-33 pubmed publisher
    ..Thus, these findings reveal links between the control mechanisms for apoptosis and cell growth. ..
  8. Yuan J, Horvitz H. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development. 1992;116:309-20 pubmed
    ..The Ced-4 protein, as deduced from cDNA and genomic DNA clones, is 549 amino acids in length. Two regions of the putative Ced-4 protein product show some similarity to known calcium-binding domains. ..
  9. Geng X, Shi Y, Nakagawa A, Yoshina S, Mitani S, Shi Y, et al. Inhibition of CED-3 zymogen activation and apoptosis in Caenorhabditis elegans by caspase homolog CSP-3. Nat Struct Mol Biol. 2008;15:1094-101 pubmed publisher
    ..However, CSP-3 does not block CED-3 activation induced by CED-4, nor does it inhibit the activity of the activated CED-3 protease. Therefore CSP-3 uses a previously unreported mechanism to protect cells from apoptosis. ..
  10. Liu W, Lin Y, Wang J, Liou W, Hou R, Wu Y, et al. Restriction of vaccinia virus replication by a ced-3 and ced-4-dependent pathway in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2006;103:4174-9 pubmed
    ..Therefore, the core PCD genes possess a unique function in controlling vaccinia virus replication in C. elegans. ..
  11. Park D, Jia H, Rajakumar V, Chamberlin H. Pax2/5/8 proteins promote cell survival in C. elegans. Development. 2006;133:4193-202 pubmed
    ..elegans bcl-2 gene. These results identify a mechanism for Pax2/5/8-mediated regulation of cell death, and underscore the importance of transcriptional regulation of core apoptotic pathway genes in influencing cell survival. ..
  12. Seiffert B, Vier J, Hacker G. Subcellular localization, oligomerization, and ATP-binding of Caenorhabditis elegans CED-4. Biochem Biophys Res Commun. 2002;290:359-65 pubmed
    ..ATP hydrolysis was required neither for complex stability nor for binding of CED-3. These features are likely to be relevant for CED-4's function as a caspase adapter. ..
  13. Wu D, Chen P, Chen S, Hu Y, Nunez G, Ellis R. C. elegans MAC-1, an essential member of the AAA family of ATPases, can bind CED-4 and prevent cell death. Development. 1999;126:2021-31 pubmed
    ..These results suggest that MAC-1 identifies a new class of proteins that are essential for development, and which might regulate cell death in specific circumstances. ..
  14. Spector M, Desnoyers S, Hoeppner D, Hengartner M. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature. 1997;385:653-6 pubmed
    ..elegans cell death by binding to and regulating CED-4 activity. We propose that mammalian Bcl-2 family members might control apoptosis in a similar way through interaction and regulation of CED-4 homologues or analogues. ..
  15. Chen X, Wang Y, Chen Y, Harry B, Nakagawa A, Lee E, et al. Regulation of CED-3 caspase localization and activation by C. elegans nuclear-membrane protein NPP-14. Nat Struct Mol Biol. 2016;23:958-964 pubmed publisher
    ..Our results reveal a critical role of nuclei and nuclear-membrane proteins in regulating the activation and localization of CED-3. ..
  16. Yan N, Gu L, Kokel D, Chai J, Li W, Han A, et al. Structural, biochemical, and functional analyses of CED-9 recognition by the proapoptotic proteins EGL-1 and CED-4. Mol Cell. 2004;15:999-1006 pubmed
    ..These data suggest a working mechanism for the release of CED-4 from the CED-4/CED-9 complex upon EGL-1 binding and provide a mechanistic framework for understanding apoptosis activation in C. elegans. ..
  17. Conradt B, Wu Y, Xue D. Programmed Cell Death During Caenorhabditis elegans Development. Genetics. 2016;203:1533-62 pubmed publisher
    ..Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. ..
  18. Chaudhary D, O Rourke K, Chinnaiyan A, Dixit V. The death inhibitory molecules CED-9 and CED-4L use a common mechanism to inhibit the CED-3 death protease. J Biol Chem. 1998;273:17708-12 pubmed
    ..These results provide a simple mechanism for how CED-9 functions to block CED-4-mediated CED-3 processing and cell death. ..
  19. Erdélyi P, Borsos E, Takacs Vellai K, Kovacs T, Kovacs A, Sigmond T, et al. Shared developmental roles and transcriptional control of autophagy and apoptosis in Caenorhabditis elegans. J Cell Sci. 2011;124:1510-8 pubmed publisher
    ..The identification of apoptosis and autophagy as compensatory cellular pathways in C. elegans might help us to understand how dysregulated PCD in humans can lead to diverse pathologies, including cancer, neurodegeneration and diabetes. ..
  20. Wu D, Wallen H, Inohara N, Nunez G. Interaction and regulation of the Caenorhabditis elegans death protease CED-3 by CED-4 and CED-9. J Biol Chem. 1997;272:21449-54 pubmed
    ..Thus, these results provide evidence that CED-4 and CED-9 regulate the activity of CED-3 through physical interactions, which may provide a molecular basis for the control of programmed cell death in C. elegans. ..
  21. Chinnaiyan A, Chaudhary D, O Rourke K, Koonin E, Dixit V. Role of CED-4 in the activation of CED-3. Nature. 1997;388:728-9 pubmed
  22. Chiorazzi M, Rui L, Yang Y, Ceribelli M, Tishbi N, Maurer C, et al. Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma. Proc Natl Acad Sci U S A. 2013;110:3943-8 pubmed publisher
    ..Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis...
  23. Parrish J, Metters H, Chen L, Xue D. Demonstration of the in vivo interaction of key cell death regulators by structure-based design of second-site suppressors. Proc Natl Acad Sci U S A. 2000;97:11916-21 pubmed
    ..The structure-based design of second-site suppressors via homology modeling should be widely applicable for probing important molecular interactions that are implicated in fundamental biological processes. ..
  24. Borsos E, Erdélyi P, Vellai T. Autophagy and apoptosis are redundantly required for C. elegans embryogenesis. Autophagy. 2011;7:557-9 pubmed
    ..This novel function of autophagy genes in morphogenesis indicates a more fundamental role for cellular self-digestion in tissue patterning than previously thought. ..
  25. Ottilie S, Wang Y, Banks S, Chang J, Vigna N, Weeks S, et al. Mutational analysis of the interacting cell death regulators CED-9 and CED-4. Cell Death Differ. 1997;4:526-33 pubmed
    ..Lastly, we show that a BH3 peptide that can inhibit Bcl-2 family interactions also inhibits the interaction between Bcl-x(L) and CED-4. ..
  26. Han J, Wallen H, Nunez G, White E. E1B 19,000-molecular-weight protein interacts with and inhibits CED-4-dependent, FLICE-mediated apoptosis. Mol Cell Biol. 1998;18:6052-62 pubmed
    ..Thus, E1B 19K functions through interacting with CED-4, and presumably a mammalian homologue of CED-4, to inhibit caspase activation and apoptosis. ..
  27. Tzur Y, Margalit A, Melamed Book N, Gruenbaum Y. Matefin/SUN-1 is a nuclear envelope receptor for CED-4 during Caenorhabditis elegans apoptosis. Proc Natl Acad Sci U S A. 2006;103:13397-402 pubmed
    ..The finding that matefin/SUN-1 is required for the execution of apoptosis adds an important link between cytoplasmic and nuclear apoptotic events. ..
  28. Parrish J, Yang C, Shen B, Xue D. CRN-1, a Caenorhabditis elegans FEN-1 homologue, cooperates with CPS-6/EndoG to promote apoptotic DNA degradation. EMBO J. 2003;22:3451-60 pubmed
    ..Our results suggest that CRN-1/FEN-1 may play a critical role in switching the state of cells from DNA replication/repair to DNA degradation during apoptosis. ..
  29. Huang W, Jiang T, Choi W, Qi S, Pang Y, Hu Q, et al. Mechanistic insights into CED-4-mediated activation of CED-3. Genes Dev. 2013;27:2039-48 pubmed publisher
    ..The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation. ..
  30. Irmler M, Hofmann K, Vaux D, Tschopp J. Direct physical interaction between the Caenorhabditis elegans 'death proteins' CED-3 and CED-4. FEBS Lett. 1997;406:189-90 pubmed
    ..Similarly, CED-4 was found to interact with CED-3. Thus, the activity of the death protease CED-3 appears to be controlled by CED-4 through a direct physical interaction. ..
  31. Contreras V, Friday A, Morrison J, Hao E, Keiper B. Cap-independent translation promotes C. elegans germ cell apoptosis through Apaf-1/CED-4 in a caspase-dependent mechanism. PLoS ONE. 2011;6:e24444 pubmed publisher
    ..These findings support a new paradigm in which modal changes in protein synthesis act as a physiological signal to initiate cell death, rather than occur merely as downstream consequences of the apoptotic event. ..
  32. Denning D, Hatch V, Horvitz H. 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. 2013;9:e1003341 pubmed publisher
    ..We conclude that both caspase-dependent and caspase-independent pathways promote apoptotic programmed cell death and the phagocytosis of cell corpses in parallel to the canonical apoptosis pathway involving CED-3 activation. ..
  33. Fairlie W, Perugini M, Kvansakul M, Chen L, Huang D, Colman P. CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13. Cell Death Differ. 2006;13:426-34 pubmed
    ..Surprisingly, the ability of worm BH3 domains to dissociate CED-4 was specific since mammalian BH3-only proteins could not do so. ..
  34. Meng L, Mulcahy B, Cook S, Neubauer M, Wan A, Jin Y, et al. The Cell Death Pathway Regulates Synapse Elimination through Cleavage of Gelsolin in Caenorhabditis elegans Neurons. Cell Rep. 2015;11:1737-48 pubmed publisher
    ..Our data suggest that activation of the CED pathway contributes to selective elimination of synapses through disassembly of the actin filament network. ..
  35. Joshi P, Eisenmann D. The Caenorhabditis elegans pvl-5 gene protects hypodermal cells from ced-3-dependent, ced-4-independent cell death. Genetics. 2004;167:673-85 pubmed
    ..elegans. This suggests that loss of pvl-5 function leads to the activation of a ced-3-dependent, ced-4-independent form of PCD and that pvl-5 may normally function to protect cells from inappropriate activation of the apoptotic pathway. ..