Interaction between the C. elegans cell-death regulators CED-9 and CED-4

Spector, Mona S.; Desnoyers, Serge; Hoeppner, Daniel J.; Hengartner, Michael O.

doi:10.1038/385653a0

Cited by 293 publications

(165 citation statements)

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“…29 While we cannot eliminate the possibility that the CED-4/CED-9 complex known to be associated with the mitochondrial membrane in the worm exists in a different oligomeric form to that described here for the E. coli-derived complex, our biochemical data for different complexes, including mutants, are consistent with the features of the protein complex characterised previously. 5,6,[8][9][10]12,15 For example, we have shown that the formation of the complex is not dependent on the presence of the CARD of CED-4, consistent with the requirement that it be free to recruit CED-3 to a trimolecular complex of CED-3/CED-4/CED-9. 7 This result agrees with other studies using yeast two-hybrid assays showing a strong interaction between CED-9 and CED-4 with its CARD deleted.…”

Section: Discussionsupporting

confidence: 78%

“…5,12,13 These have been complemented by mutational analysis of both CED-4 and CED-9. 9,10,14 Similarly, numerous studies have demonstrated the interaction between CED-9 and EGL-1, and release and/or redistribution of CED-4 from the mitochondria. 3,12,[14][15][16] Recently, three-dimensional structures were determined for the Bcl-2 homology region of CED-9 alone, 16 and in complex with an EGL-1 fragment encompassing its BH3 domain, 14 confirming the structural similarity with the mammalian Bcl-2 prosurvival family members 17,18 and their mode of engagement with BH3 domains.…”

Section: Introductionmentioning

confidence: 97%

“…5 This pathway of protein interactions has been extensively studied using a myriad of techniques. For example, interaction of CED-4 with CED-9 (and simultaneously with CED-3) has been demonstrated by co-immunoprecipitation of proteins expressed in various cell types, 6-8 the yeast two-hybrid system, [9][10][11] or by colocalization studies. 5,12,13 These have been complemented by mutational analysis of both CED-4 and CED-9.…”

Section: Introductionmentioning

confidence: 99%

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CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13

et al. 2005

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The pathway to cell death in Caenorhabditis elegans is well established. In cells undergoing apoptosis, the Bcl-2 homology domain 3 (BH3)-only protein EGL-1 binds to CED-9 at the mitochondrial membrane to cause the release of CED-4, which oligomerises and facilitates the activation of the caspase CED-3. However, despite many studies, the biophysical features of the CED-4/CED-9 complex have not been fully characterised. Here, we report the purification of a soluble and stable 2 : 2 heterotetrameric complex formed by recombinant CED-4 and CED-9 coexpressed in bacteria. Consistent with previous studies, synthetic peptides corresponding to the BH3 domains of worm BH3-only proteins (EGL-1, CED-13) dissociate CED-4 from CED-9, but not from the gain-offunction CED-9 (G169E) mutant. Surprisingly, the ability of worm BH3 domains to dissociate CED-4 was specific since mammalian BH3-only proteins could not do so.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13

et al. 2005

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“…Apaf-1 possesses a CARD domain which interacts with a similar domain within the N-terminus of pro-caspase-9 (and pro-caspase-2?). This leads to the formation of a tri-molecular complex containing Bcl-2/Bcl-X L , Apaf-1, and pro-caspase-9, in analogy to the trimolecular complex formed in C. elegans by CED9, CED4 and the pro-caspase CED3 (Spector et al, 1997). This trimolecular complex has been nick-named the`apoptosome' and may explain most features of cell death regulation in C. elegans (Hengartner, 1997).…”

Section: Indirect Interactions Between Bcl-2 and Caspasesmentioning

confidence: 99%

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

et al. 1998

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Bcl-2 is the prototype of a class of oncogenes which regulates apoptosis. Bcl-2-related gene products with either death-promoting and death-inhibitory activity are critically involved in numerous disease states and thus constitute prime targets for therapeutic interventions. The relative amount of death agonists and antagonists from the Bcl-2 family constitutes a regulatory rheostat whose function is determined, at least in part, by selective protein-protein interactions. Bcl-2 and its homologs insert into intracellular membranes including mitochondria, the endoplasmatic reticulum and the nuclear envelope. Many of the molecular genetic, ultrastructural, crystallographic and functional studies suggest that Bcl-2-related molecules exert their apoptosis-regulatory e ects via regulating mitochondrial alterations preceding the activation of apoptogenic proteases and nucleases. Via a direct e ect on mitochondrial membranes, Bcl-2 prevents all hallmarks of the early stage of apoptosis including disruption of the inner mitochondrial transmembrane potential and the release of apoptogenic protease activators from mitochondria. The mitochondrial permeability transition (PT) pore, also called mitochondrial megachannel or multiple conductance channel, is a multiprotein complex formed at the contact site between the mitochondrial inner and outer membranes, exactly at the same localization at which Bax, Bcl-2, and Bcl-X L are particularly abundant. The PT pore participates in the regulation of matrix Ca 2+ , pH, DC m , and volume and functions as a Ca 2+ -, voltage-, pH-, and redox-gated channel with several levels of conductance and little if any ion selectivity. Experiments involving the puri®ed PT pore complex indicate that Bax, Bcl-2, and Bcl-X L exert at least part of their apoptosis-regulatory function by facilitating (Bax) or inhibiting (Bcl-2, Bcl-X L ) PT pore opening. These ®ndings clarify the principal (but not exclusive) mechanism of Bcl-2-mediated cytoprotection.

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“…Similar to CED-4, and most probably to proCED-3, the anti-apoptotic CED-9 protein is present in many cells at this stage (Chen et al, 2000). CED-9 localizes to the outer mitochondrial membrane, and it is through the physical interaction between CED-9 and an asymmetric dimer of CED-4 that the ability of CED-4 to form an active apoptosome and to mediate proCED-3 activation is blocked (Spector et al, 1997;Chinnaiyan et al, 1997b;Wu et al, 1997b;Chen et al, 2000;Yan et al, 2005). In the 113 cells that are programed to die, this block is released by the EGL-1 protein.…”

mentioning

confidence: 99%

egl-1: a key activator of apoptotic cell death in C. elegans

Nehme

Conradt

2008

Oncogene

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Since the discovery of mammalian BIK and BAD in 1995, BH3-only proteins have emerged as key activators of apoptotic cell death in animals as diverse as the nematode, Caenorhabditis elegans, and humans. BH3-only proteins have also emerged as integrators of cell-death signals that determine the life-versus-death decision and that transduce this decision to the central apoptotic machinery through their physical interaction with 'core' BCL-2 family members, such as BCL-2 or BCL-XL. Currently, eight BH3-only proteins have been identified and characterized in mammals, and there is evidence of functional overlap between them. In contrast, only two BH3-only proteins have so far been identified and characterized in C. elegans, EGL-1 and CED-13, and there seems to be only limited functional overlap between them. Combined with the powerful genetic tools available for the analysis of apoptosis in C. elegans, and the ability to study apoptosis at single-cell resolution in this organism, the absence of extensive functional redundancy makes C. elegans an ideal model for studies on BH3-only proteins. In this study, we will review our current understanding of the role and regulation of EGL-1. We will also briefly summarize studies on CED-13, which was identified more recently.Oncogene ( Keywords: BCL-2 family; BH3-only proteins; apoptosis; C. elegans; EGL-1; CED-13The egl-1 storyThe egl-1 gene was originally defined by dominant, gain of function (gf) mutations (Trent et al., 1983;Ellis and Horvitz, 1986). These gf mutations cause the hermaphrodite-specific neurons (referred to as 'HSNs'), which are required for egg laying in Caenorhabditis elegans hermaphrodites, to inappropriately die. egl-1 gf mutations were identified in screens for egg-laying defective or 'Egl' animals, and were carried out in Bob Horvitz's laboratory in the early 1980s (hence the name 'egl-1'). These 'Egl screens' resulted in the identification of a total of seven egl-1 gf mutations. Three of these mutations (n487, n1084 and n1796) cause an Egl phenotype in a semi-dominant manner, and the remaining four mutations (n986, n987, n2164 and n2248) cause an Egl phenotype in a fully dominant manner. The inappropriate death of the HSNs in egl-1 gf mutants can be suppressed by mutations that cause a general block in apoptotic cell death, such as a gf mutation in ced-9, which encodes an anti-apoptotic BCL-2-like protein, or loss-of-function (lf) mutations in either ced-4 or ced-3, which encode an APAF-1-like adapter or a caspase, respectively (Ellis and Horvitz, 1986;Hengartner et al., 1992;Yuan and Horvitz, 1992;Yuan et al., 1993;Hengartner and Horvitz, 1994b). These findings showed that the HSNs in egl-1 gf animals inappropriately die by apoptosis. They also suggested that the egl-1 gene may act upstream of the anti-apoptotic gene, ced-9, and of the pro-apoptotic genes, ced-4 and ced-3; however, the normal function of egl-1 remained unclear because of the lack of egl-1 lf mutations. The lack of egl-1 lf mutations not only made it difficult to determine the normal f...

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Interaction between the C. elegans cell-death regulators CED-9 and CED-4

Cited by 293 publications

References 26 publications

CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13

CED-4 forms a 2 : 2 heterotetrameric complex with CED-9 until specifically displaced by EGL-1 or CED-13

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

egl-1: a key activator of apoptotic cell death in C. elegans

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