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Cellular Signalling Jul 2012Apoptosomes are signaling platforms that initiate the dismantling of a cell during apoptosis. In mammals, assembly of the apoptosome is the pivotal point in the... (Review)
Review
Apoptosomes are signaling platforms that initiate the dismantling of a cell during apoptosis. In mammals, assembly of the apoptosome is the pivotal point in the mitochondrial pathway of apoptosis, and is prompted by binding of cytochrome c to the apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP. The resulting wheel-like heptamer of seven molecules Apaf-1 and seven molecules cytochrome c binds and activates the initiator caspase-9, which in turn ignites the downstream caspase cascade. In this review we discuss the molecular determinants for the formation of the mammalian apoptosome and caspase activation and describe the related signaling platforms in flies and nematodes.
Topics: Adenosine Triphosphate; Animals; Apoptosis; Apoptosomes; Apoptotic Protease-Activating Factor 1; Caspase 9; Cytochromes c; Mitochondria; Protein Conformation; Protein Structure, Tertiary; Signal Transduction
PubMed: 22446004
DOI: 10.1016/j.cellsig.2012.03.007 -
Molecular Interventions Feb 2003Apoptosis (programmed cell death) is a physiological process used to eliminate superfluous, damaged, infected, or aged cells in multicellular organisms. During apoptosis... (Review)
Review
Apoptosis (programmed cell death) is a physiological process used to eliminate superfluous, damaged, infected, or aged cells in multicellular organisms. During apoptosis the cellular architecture is dismantled from within in a highly controlled fashion. Members of the caspase family of cysteine proteases are responsible for the destructive phase of apoptosis. One major pathway to caspase activation involves the formation of a multisubunit protease activation complex called the apoptosome. The apoptosome is assembled in response to signals that provoke mitochondrial outer membrane permeabilization and the release of cytochrome c into the cytosol. Recent studies indicate that the apoptosome is a wheel-like structure consisting of seven molecules of Apaf-1 and a similar number of caspase-9 dimers. Knowledge of the structure of the apoptosome will likely lead to the design of therapeutic modulators of apoptosis.
Topics: Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase 9; Caspases; Cytochrome c Group; Deoxyadenine Nucleotides; Dimerization; Enzyme Activation; Humans; Mitochondria; Models, Molecular; Proteins
PubMed: 14993435
DOI: 10.1124/mi.3.1.19 -
Cell Death & Disease May 2020Caspase-2, -9, and -3 are reported to control myoblast differentiation into myotubes. This had been previously explained by phosphatidylserine exposure on apoptotic...
Caspase-2, -9, and -3 are reported to control myoblast differentiation into myotubes. This had been previously explained by phosphatidylserine exposure on apoptotic myoblasts inducing differentiation in neighboring cells. Here we show for the first time that caspase-3 is activated in the myoblasts undergoing differentiation. Using RNAi, we also demonstrate that differentiation requires both cytochrome c and Apaf-1, and by using a new pharmacological approach, we show that apoptosome formation is required. We also show that Bid, whose cleavage links caspase-2 to the mitochondrial death pathway, was required for differentiation, and that the caspase cleavage product, tBid, was generated during differentiation. Taken together, these data suggest that myoblast differentiation requires caspase-2 activation of the mitochondrial death pathway, and that this occurs in the cells that differentiate. Our data also reveal a hierarchy of caspases in differentiation with caspase-2 upstream of apoptosome activation, and exerting a more profound control of differentiation, while caspases downstream of the apoptosome primarily control cell fusion.
Topics: Animals; Apoptosis; Apoptosomes; Apoptotic Protease-Activating Factor 1; BH3 Interacting Domain Death Agonist Protein; Caspase 2; Caspase 3; Caspase Inhibitors; Cell Differentiation; Cell Fusion; Cell Line; Cyclohexanones; Cytochromes c; Enzyme Activation; Gene Knockdown Techniques; Humans; Mice; Muscle Fibers, Skeletal; Myoblasts; RNA, Small Interfering
PubMed: 32366831
DOI: 10.1038/s41419-020-2502-4 -
Drug Metabolism Reviews Nov 2003Many environmental and therapeutic agents initiate apoptotic cell death by inducing the release of cytochrome c from the mitochondria, which activates Apaf-1 (apoptotic... (Review)
Review
Many environmental and therapeutic agents initiate apoptotic cell death by inducing the release of cytochrome c from the mitochondria, which activates Apaf-1 (apoptotic protease-activating factor-1). This large (approximately 130kD) protein is a mammalian homologue of CED-4, an essential protein involved in programmed cell death in the nematode C. elegans. Cytochrome c activates Apaf-1, which oligomerizes to form an approximately 700-1400-kDa caspase-activating complex known as the Apaf-1 apoptosome. Caspase-9, an initiator caspase, is then recruited to the complex by binding to Apaf-1 through CARD-CARD (caspase recruitment domain) interactions to form a holoenzyme complex. Subsequently, the Apaf-1/caspase-9 holoenzyme complex recruits the effector caspase-3 via an interaction between the active site cysteine in caspase-9 and the critical aspartate, which is the cleavage site for generating the large and small subunits of caspase-3 that constitute the activated form of caspase-3. This initiates the caspase cascade that is responsible for the execution phase of apoptosis. Intracellular levels of K+, XIAP an inhibitor of apoptosis protein, and at least two mitochondrial released proteins, Smac/DIABLO and Omi/Htra 2 a serine protease, tightly regulate formation and function of the apoptosome. Thus, a number of physiological mechanisms ensure that the apoptosome complex is only fully assembled and functional when the cell is irrevocably committed to die. It is interesting that more recent studies show that a variety of small molecules can directly activate or inhibit caspase activation by interfering with the formation and function of the apoptosome complex. The cytotoxicity of many conventional chemotherapeutic drugs rests on their ability to induce apoptosome formation and apoptosis. Defects in this pathway can result in drug resistance, and the discovery that small molecules can directly activate or inhibit the apoptosome may provide new alternative treatments for cancer.
Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase 9; Caspases; Humans; Pharmaceutical Preparations; Proteins
PubMed: 14705865
DOI: 10.1081/dmr-120026497 -
Genes To Cells : Devoted To Molecular &... Nov 1998Apoptosis is an essential physiological process for the selective elimination of cells, which is involved in a variety of biological events. The Bcl-2 family is the best... (Review)
Review
Apoptosis is an essential physiological process for the selective elimination of cells, which is involved in a variety of biological events. The Bcl-2 family is the best characterized protein family involved in the regulation of apoptotic cell death, consisting of anti-apoptotic and pro-apoptotic members. The anti-apoptotic members of this family, such as Bcl-2 and Bcl-XL, prevent apoptosis either by sequestering proforms of death-driving cysteine proteases called caspases (a complex called the apoptosome) or by preventing the release of mitochondrial apoptogenic factors such as cytochrome c and AIF (apoptosis-inducing factor) into the cytoplasm. After entering the cytoplasm, cytochrome c and AIF directly activate caspases that cleave a set of cellular proteins to cause apoptotic changes. In contrast, pro-apoptotic members of this family, such as Bax and Bak, trigger the release of caspases from death antagonists via heterodimerization and also by inducing the release of mitochondrial apoptogenic factors into the cytoplasm via acting on mitochondrial permeability transition pore, thereby leading to caspase activation. Thus, the Bcl-2 family of proteins acts as a critical life-death decision point within the common pathway of apoptosis.
Topics: Animals; Apoptosis; Caenorhabditis elegans; Mitochondria; Organelles; Protein Binding; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-bcl-2
PubMed: 9990505
DOI: 10.1046/j.1365-2443.1998.00223.x -
The Biochemical Journal Feb 2022Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis and eliminates potentially dangerous cells. Apoptosis,...
Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis and eliminates potentially dangerous cells. Apoptosis, one of the better-known forms of regulated cell death, is activated when cell-surface death receptors like Fas are engaged by their ligands (the extrinsic pathway) or when BCL-2-family pro-apoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both the intrinsic and extrinsic pathways of apoptosis lead to the activation of a family of proteases, the caspases, which are responsible for the final cell demise in the so-called execution phase of apoptosis. In this review, I will first discuss the most common types of regulated cell death on a morphological basis. I will then consider in detail the molecular pathways of intrinsic and extrinsic apoptosis, discussing how they are activated in response to specific stimuli and are sometimes overlapping. In-depth knowledge of the cellular mechanisms of apoptosis is becoming more and more important not only in the field of cellular and molecular biology but also for its translational potential in several pathologies, including neurodegeneration and cancer.
Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Apoptosomes; Autophagy; Caspases; Humans; Invertebrates; Ligands; Lysosomes; Macrophages; Mitochondrial Membranes; Necrosis; Neoplasm Proteins; Permeability; Phagocytosis; Proto-Oncogene Proteins c-bcl-2; Receptors, Death Domain
PubMed: 35147165
DOI: 10.1042/BCJ20210854 -
Journal of Molecular and Cellular... Sep 2004Apoptosis is a form of cell death which utilizes energy resources to dismantle and remove cells in an orderly or programmed fashion. It plays an essential role in... (Review)
Review
Apoptosis is a form of cell death which utilizes energy resources to dismantle and remove cells in an orderly or programmed fashion. It plays an essential role in establishing normal embryonic development, maintaining adult tissue homeostasis and contributes to a variety of human diseases including certain pathological processes in the heart. Apoptosis is mediated by a distinct biochemical pathway that is conserved in multicellular organisms. Signaling for apoptosis is initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway). In both pathways, signaling results in the activation of a family of cysteine proteases, named caspases, that act in a proteolytic cascade to dismantle and remove the dying cell. The activation of the intrinsic death pathway involves the release of cytochrome c from the mitochondria and formation of the apoptosome, a catalytic multiprotein platform that activates caspase-9. There is evidence that the mitochondrial pathway is involved in ischemia-induced myocyte apoptosis in the heart. Diminished expression of pro-apoptotic factors and/or expression of certain inhibitors of the apoptosome may raise the threshold for apoptosis in long-lived post-mitotic cells including myocytes of the heart.
Topics: Animals; Apoptosis; Caspase 9; Caspases; Cytochromes c; Humans; Mitochondria, Heart; Multiprotein Complexes; Myocardial Ischemia; Myocardium; Signal Transduction
PubMed: 15350837
DOI: 10.1016/j.yjmcc.2004.04.016 -
Nature Communications Apr 2019Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that...
Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway.
Topics: Animals; Caspase 3; Cytochromes c; Fibroblasts; Gene Knockout Techniques; HEK293 Cells; HeLa Cells; Humans; Inflammasomes; Macrophages; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Membranes; Mutation; Phosphorylation; Primary Cell Culture; Protein Domains; Pyroptosis; Receptors, Estrogen; Skin Neoplasms; Threonine
PubMed: 30976076
DOI: 10.1038/s41467-019-09397-2 -
Cell Death and Differentiation Mar 2008Apoptosis, a form of programmed cell death, enables organisms to maintain tissue homeostasis through deletion of extraneous cells and also serves as a means to eliminate... (Review)
Review
Apoptosis, a form of programmed cell death, enables organisms to maintain tissue homeostasis through deletion of extraneous cells and also serves as a means to eliminate potentially harmful cells. Numerous stress signals have been shown to engage the intrinsic pathway of apoptosis, with the release from mitochondria of proapoptotic factors such as cytochrome c and the subsequent formation of a cytosolic complex between apoptotic protease-activating factor-1 (Apaf-1) and procaspase-9, known as the apoptosome. Recent studies have led to the identification of an array of factors that control the formation and activation of the apoptosome under physiological conditions. Moreover, deregulation of apoptosome function has been documented in various forms of human cancer, and may play a role in both carcinogenesis and chemoresistance. We discuss how the apoptosome is regulated in normal and disease states, and how targeting of apoptosome-dependent, post-mitochondrial stages of apoptosis may serve as a rational approach to cancer treatment.
Topics: Animals; Apoptosis; Apoptosomes; Apoptotic Protease-Activating Factor 1; Caspases; Cytochromes c; Drug Resistance, Neoplasm; Humans; Mice; Neoplasms; Signal Transduction
PubMed: 17975549
DOI: 10.1038/sj.cdd.4402265 -
Experimental Cell Research Jul 2012Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in... (Review)
Review
Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling.
Topics: Animals; Apoptosis; Apoptosomes; Caspase 9; Caspases, Initiator; Humans; Signal Transduction
PubMed: 22406265
DOI: 10.1016/j.yexcr.2012.02.013