Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans

Yan, Nieng; Chai, Jijie; Lee, Eui Seung; Gu, Lichuan; Liu, Qun; He, Jiaqing; Wu, Jiawei; Kokel, David; Li, Huilin; Hao, Quan; Xue, Ding; Shi, Yigong

doi:10.1038/nature04002

“…Recent structural and biochemical data demonstrate that CED-3 is activated by a tetrameric CED-4 complex (apoptosome) that is prevented from assembling by interaction with CED-9 until EGL-1 sequesters CED-9 away. 13 In healthy cells, CED-4 is a dimer directly bound to CED-9, and presumably this interaction prevents CED-4 activation by tetramerization. 13 The elevated levels of EGL-1, primarily regulated by transcription in response to developmental cues, allow sequestration of CED-9 and release of CED-4.…”

Section: Ced-3 the Death Caspase In C Elegansmentioning

confidence: 99%

“…13 In healthy cells, CED-4 is a dimer directly bound to CED-9, and presumably this interaction prevents CED-4 activation by tetramerization. 13 The elevated levels of EGL-1, primarily regulated by transcription in response to developmental cues, allow sequestration of CED-9 and release of CED-4. Following the release from CED-9, two CED-4 dimers form the active tetramer that recruits and facilitates CED-3 activation.…”

Section: Ced-3 the Death Caspase In C Elegansmentioning

confidence: 99%

Caspase function in programmed cell death

Kumar

¹

2006

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The first proapoptotic caspase, CED-3, was cloned from Caenorhabditis elegans in 1993 and shown to be essential for the developmental death of all somatic cells. Following the discovery of CED-3, caspases have been cloned from several vertebrate and invertebrate species. As reviewed in other articles in this issue of Cell Death and Differentiation, many caspases function in nonapoptotic pathways. However, as is clear from the worm studies, the evolutionarily conserved role of caspases is to execute programmed cell death. In this article, I will specifically focus on caspases that function primarily in cell death execution. In particular, the physiological function of caspases in apoptosis is discussed using examples from the worm, fly and mammals.

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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%

“…The interaction of EGL-1 with CED-9/ CED-4 complexes induces a dramatic structural change in CED-9, which alters its CED-4-binding site and results in the release of the CED-4 dimer (Conradt and Horvitz, 1998;del Peso et al, 1998del Peso et al, , 2000Chen et al, 2000;Yan et al, 2004). CED-4 dimers released from the mitochondria-localized EGL-1/CED-9 complex relocalize to perinuclear membranes and assemble into active apoptosomes (which most probably are homotetramers), capable of mediating proCED-3 activation (Irmler et al, 1997;Seshagiri and Miller, 1997 Yan et al, 2005). Once activated, the mature CED-3 caspase induces processes that result in the demise of the cell.…”

mentioning

confidence: 99%

“…Once activated, the mature CED-3 caspase induces processes that result in the demise of the cell. Much of the mechanistic insight into this step of apoptosis induction in C. elegans is based on structural studies carried out by Ding Xue, Yigong Shi et al (Yan et al, 2004(Yan et al, , 2005, who solved the crystal structure of CED-9 bound to either CED-4 or part of EGL-1. With a 100 different complexes and over 30 000 crystallization conditions, obtaining crystals of the EGL-1/CED-9 complex required a heroic effort, but resulted in the discovery of fascinating clues regarding the molecular mechanisms involved in apoptosis induction in C. elegans.…”

mentioning

confidence: 99%

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

Nehme

¹

,

Conradt

²

2008

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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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Cell Death inC. elegans

Sendoel

¹

,

Hengartner

²

2009

Encyclopedia of Life Sciences

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Programmed cell death plays a central role in the development of most multicellular animals. During the development of Caenorhabditis elegans , a total of 1090 cells are generated, 131 of which are destined to die. Genetic studies focusing on the control of the fate of these 131 cells revealed an evolutionary conserved set of genes essential for all programmed cell deaths in C. elegans . In a cell undergoing apoptosis, the BH3‐only domain protein EGL‐1 binds to the CED‐9–CED‐4 complex on the outer mitochondrial membrane resulting in the release of CED‐4 , which in turn activates the effector caspase CED‐3 . These at the time pioneering findings established C. elegans as a prime model system to study apoptosis, a system that still today provides a stage for new inspiring science, such as studies on C. elegans apoptotic cell clearance and on deoxyribonucleic acid (DNA) damage‐induced apoptosis. Key concepts: Caenorhabditis elegans as a model organism has been introduced by Sidney Brenner in the 1960s. The complete C. elegans cell lineage was described in 1983 by John Sulston. The cell lineage in C. elegans is invariant: during the development of an animal, a total of 1090 cells are generated, 131 of which are destined to die. The basis for analysing programmed cell death in C. elegans was delineation of the complete cell lineage. There are three waves of programmed cell death in C. elegans : a first wave can be observed in embryos, the second smaller wave during the second larval stage, whereas the third wave occurs in the adult germline. Germline apoptosis is a stochastic process in which half of the germ cells undergo apoptotic cell death. CED‐4 and CED‐3 are killer proteins essential for all programmed cell deaths in C. elegans . CED‐9 is homologous to Bcl‐2 and protects from cell death. In a cell undergoing apoptosis, the BH3‐only domain protein EGL‐1 inhibits CED‐9 from inhibiting CED‐4. The central cell death pathway is conserved through evolution; homologues of EGL‐1, CED‐9, CED‐4 and CED‐3 are present in mammals, where they control the mitochondrial pathway for apoptosis. Apoptotic cell clearance is controlled via two partially redundant intracellular signalling cascades that converge at the Rac1 homologue CED‐10. DNA damage‐induced germline apoptosis is triggered by a genomic integrity checkpoint and activates a pathway including the p53 homologue CEP‐1.

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Structure of the CED-4–CED-9 complex provides insights into programmed cell death in Caenorhabditis elegans

Cited by 200 publications

References 39 publications

Caspase function in programmed cell death

Caspase function in programmed cell death

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

Cell Death inC. elegans

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