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Journal articles on the topic 'Apoptosoma'

Author: Grafiati

Published: 4 June 2021

Last updated: 18 February 2022

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1

Chai, Jijie, and Yigong Shi. "Apoptosome and inflammasome: conserved machineries for caspase activation." National Science Review 1, no. 1 (2014): 101–18. http://dx.doi.org/10.1093/nsr/nwt025.

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Abstract Apoptosome and inflammasome are multimeric protein complexes that mediate the activation of specific caspases at the onset of apoptosis and inflammation. The central component of apoptosome or inflammasome is a tripartite scaffold protein, exemplified by Apaf-1 and NLRC4, which contains an amino-terminal homotypic interaction motif, a central nucleotide-binding oligomerization domain and a carboxyl-terminal ligand-sensing domain. In the absence of death cue or an inflammatory signal, Apaf-1 or NLRC4 exists in an auto-inhibited, monomeric state, which is stabilized by adenosine diphosphate (ADP). Binding to an apoptosis- or inflammation-inducing ligand, together with replacement of ADP by adenosine triphosphate (ATP), results in the formation of a multimeric apoptosome or inflammasome. The assembled apoptosome and inflammasome serve as dedicated machineries to facilitate the activation of specific caspases. In this review, we describe the structure and functional mechanisms of mammalian inflammasome and apoptosomes from three representative organisms. Emphasis is placed on the molecular mechanism of caspase activation and the shared features of apoptosomes and inflammasomes.

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2

Beem, Elaine, L. Shannon Holliday, and Mark S. Segal. "The 1.4-MDa apoptosome is a critical intermediate in apoptosome maturation." American Journal of Physiology-Cell Physiology 287, no. 3 (2004): C664—C672. http://dx.doi.org/10.1152/ajpcell.00232.2003.

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Previously, we demonstrated that both 150 mM KCl and alkaline pH inhibit cytochrome c-mediated activation of procaspase-3 in a unique manner. To determine the mechanism of inhibition, we analyzed the effect of KCl and alkaline pH on the formation of apoptosomes (a large complex consisting of cytochrome c, Apaf-1, and procaspase-9/caspase-9) in vitro. Our results suggest that an initial ∼700-kDa apoptosome matures through a 1.4-MDa intermediate before a ∼700-kDa apoptosome is reformed and procaspase-3 is activated. We further demonstrate that 150 mM KCl interferes with the conversion of the initial ∼700-kDa apoptosome to the 1.4-MDa intermediate, while alkaline pH “traps” the apoptosome in the 1.4-MDa intermediate. Analysis of the cleaved state of procaspase-9 and procaspase-3 suggests that the 1.4-MDa intermediate may be required for cleavage of procaspase-9. Consistent with these results, in vivo data suggest that blocking acidification during the induction of apoptosis inhibits activation of procaspase-3. On the basis of these results, we propose a model of apoptosome maturation.

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3

Murphy, Brona M., Amanda J. O'Neill, Colin Adrain, R. William G. Watson, and Seamus J. Martin. "The Apoptosome Pathway to Caspase Activation in Primary Human Neutrophils Exhibits Dramatically Reduced Requirements for Cytochrome c." Journal of Experimental Medicine 197, no. 5 (2003): 625–32. http://dx.doi.org/10.1084/jem.20021862.

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Caspase activation is a central event in numerous forms of apoptosis and results in the proteolytic degradation of multiple substrate proteins that contribute to the apoptotic phenotype. An important route to caspase activation proceeds via assembly of the “apoptosome” as a result of the cell stress–associated release of mitochondrial cytochrome c. Previous studies have shown that primary neutrophils are largely incapable of mitochondrial respiration, suggesting that these cells either lack functional mitochondria or possess a defective respiratory chain. This prompted us to examine whether neutrophils retain an intact cytochrome c/apoptotic protease-activating factor 1 (Apaf-1) pathway to caspase activation and apoptosis. We show that primary human neutrophils contain barely detectable levels of cytochrome c as well as other mitochondrial proteins. Surprisingly, neutrophil cell–free extracts readily supported Apaf-1–dependent caspase activation, suggesting that these cells may assemble cytochrome c–independent apoptosomes. However, further analysis revealed that the trace amount of cytochrome c present in neutrophils is both necessary and sufficient for Apaf-1–dependent caspase activation in these cells. Thus, neutrophils have a lowered threshold requirement for cytochrome c in the Apaf-1–dependent cell death pathway. These observations suggest that neutrophils retain cytochrome c for the purpose of assembling functional apoptosomes rather than for oxidative phosphorylation.

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4

Suto, Daisuke, Kazuaki Sato, Yoshihiro Ohba, Tetsuhiko Yoshimura, and Junichi Fujii. "Suppression of the pro-apoptotic function of cytochrome c by singlet oxygen via a haem redox state-independent mechanism." Biochemical Journal 392, no. 2 (2005): 399–406. http://dx.doi.org/10.1042/bj20050580.

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Stimuli for apoptotic signalling typically induce release of cyt c (cytochrome c) from mitochondria. Cyt c then initiates the formation of the apoptosome, comprising Apaf-1 (apoptotic protease-activating factor 1), caspase-9 and other cofactors. The issue of whether the redox state of the haem in cyt c affects the initiation of the apoptotic pathway is currently a subject of debate. In a cell-free reconstitution system, we found that only oxidized cyt c was capable of activating the caspase cascade. Oxidized cyt c was reduced by the physiological reductants cysteine and glutathione, after which it was unable to activate the caspase cascade. It is thus likely that cyt c with oxidized haem is in a conformation capable of interaction with Apaf-1 and forming apoptosomes. When either oxidized or reduced cyt c was treated with submillimolar concentrations of endoperoxide, which affected less than 3% of the redox state of haem, the ability of the oxidized cyt c to activate the caspase cascade was abolished. Higher amounts of singlet oxygen were required to affect the optical spectral change of haem, suggesting that the suppressed pro-apoptotic function of oxidized cyt c is a mechanism that is separate from the redox state of haem. Oxidative protein modification of cyt c by singlet oxygen was evident, on the basis of elevated contents of carbonyl compounds. Our data suggest that singlet oxygen eliminates the pro-apoptotic ability of oxidized cyt c not via the reduction of haem, but via the modification of amino acid residues that are required for apoptosome formation.

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5

Salvesen, Guy S., and Martin Renatus. "Apoptosome." Developmental Cell 2, no. 3 (2002): 256–57. http://dx.doi.org/10.1016/s1534-5807(02)00137-5.

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6

Shi, Yigong. "Apoptosome." Structure 10, no. 3 (2002): 285–88. http://dx.doi.org/10.1016/s0969-2126(02)00732-3.

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7

Kurokawa, Manabu, Chen Zhao, Tannishtha Reya та Sally Kornbluth. "Inhibition of Apoptosome Formation by Suppression of Hsp90β Phosphorylation in Tyrosine Kinase-Induced Leukemias". Molecular and Cellular Biology 28, № 17 (2008): 5494–506. http://dx.doi.org/10.1128/mcb.00265-08.

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ABSTRACT Constitutively active tyrosine kinases promote leukemogenesis by increasing cell proliferation and inhibiting apoptosis. However, mechanisms underlying apoptotic inhibition have not been fully elucidated. In many settings, apoptosis occurs by mitochondrial cytochrome c release, which nucleates the Apaf-1/caspase-9 apoptosome. Here we report that the leukemogenic kinases, Bcr-Abl, FLT3/D835Y, and Tel-PDGFRβ, all can inhibit apoptosome function. In cells expressing these kinases, the previously reported apoptosome inhibitor, Hsp90β, bound strongly to Apaf-1, preventing cytochrome c-induced Apaf-1 oligomerization and caspase-9 recruitment. Hsp90β interacted weakly with the apoptosome in untransformed cells. While Hsp90β was phosphorylated at Ser 226/Ser 255 in untransformed cells, phosphorylation was absent in leukemic cells. Expression of mutant Hsp90β (S226A/S255A), which mimics the hypophosphorylated form in leukemic cells, conferred resistance to cytochrome c-induced apoptosome activation in normal cells, reflecting enhanced binding of nonphosphorylatable Hsp90β to Apaf-1. In Bcr-Abl-positive mouse bone marrow cells, nonphosphorylatable Hsp90β expression conferred imatinib (Gleevec) resistance. These data provide an explanation for apoptosome inhibition by activated leukemogenic tyrosine kinases and suggest that alterations in Hsp90β-apoptosome interactions may contribute to chemoresistance in leukemias.

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8

Twiddy, Davina, David G. Brown, Colin Adrain, et al. "Pro-apoptotic Proteins Released from the Mitochondria Regulate the Protein Composition and Caspase-processing Activity of the Native Apaf-1/Caspase-9 Apoptosome Complex." Journal of Biological Chemistry 279, no. 19 (2004): 19665–82. http://dx.doi.org/10.1074/jbc.m311388200.

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The apoptosome is a large caspase-activating (∼700–1400 kDa) complex, which is assembled from Apaf-1 and caspase-9 when cytochromecis released during mitochondrial-dependent apoptotic cell death. Apaf-1 the core scaffold protein is ∼135 kDa and contains CARD (caspaserecruitmentdomain), CED-4, and multiple (13) WD40 repeat domains, which can potentially interact with a variety of unknown regulatory proteins. To identify such proteins we activated THP.1 lysates with dATP/cytochromecand used sucrose density centrifugation and affinity-based methods to purify the apoptosome for analysis by MALDI-TOF mass spectrometry. First, we used a glutathioneS-transferase (GST) fusion protein (GST-casp91–130) containing the CARD domain of caspase-9-(1–130), which binds to the CARD domain of Apaf-1 when it is in the apoptosome and blocks recruitment/activation of caspase-9. This affinity-purified apoptosome complex contained only Apaf-1XL and GST-casp91–130, demonstrating that the WD40 and CED-4 domains of Apaf-1 do not stably bind other cytosolic proteins. Next we used a monoclonal antibody to caspase-9 to immunopurify the native active apoptosome complex from cell lysates, containing negligible levels of cytochromec,secondmitochondria-derivedactivator ofcaspase (Smac), or Omi/HtrA2. This apoptosome complex exhibited low caspase-processing activity and contained four stably associated proteins, namely Apaf-1, pro-p35/34 forms of caspase-9, pro-p20 forms of caspase-3, X-linkedinhibitor ofapoptosis (XIAP), and cytochromec, which was only bound transiently to the complex. However, in lysates containing Smac and Omi/HtrA2, the caspase-processing activity of the purified apoptosome complex increased 6–8-fold and contained only Apaf-1 and the p35/p34-processed subunits of caspase-9. During apoptosis, Smac, Omi/HtrA2, and cytochromecare released simultaneously from mitochondria, and thus it is likely that the functional apoptosome complex in apoptotic cells consists primarily of Apaf-1 and processed caspase-9.

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9

Ho, Andrew T., and Eldad Zacksenhaus. "Splitting the Apoptosome." Cell Cycle 3, no. 4 (2004): 444–46. http://dx.doi.org/10.4161/cc.3.4.818.

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10

Lademann, Ulrik, Kelvin Cain, Mads Gyrd-Hansen, David Brown, Dan Peters, and Marja Jäättelä. "Diarylurea Compounds Inhibit Caspase Activation by Preventing the Formation of the Active 700-Kilodalton Apoptosome Complex." Molecular and Cellular Biology 23, no. 21 (2003): 7829–37. http://dx.doi.org/10.1128/mcb.23.21.7829-7837.2003.

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ABSTRACT The release of mitochondrial proapoptotic proteins into the cytosol is the key event in apoptosis signaling, leading to the activation of caspases. Once in the cytosol, cytochrome c triggers the formation of a caspase-activating protein complex called the apoptosome, whereas Smac/Diablo and Omi/htra2 antagonize the caspase inhibitory effect of inhibitor of apoptosis proteins (IAPs). Here, we identify diarylurea compounds as effective inhibitors of the cytochrome c-induced formation of the active, approximately 700-kDa apoptosome complex and caspase activation. Using diarylureas to inhibit the formation of the apoptosome complex, we demonstrated that cytochrome c, rather than IAP antagonists, is the major mitochondrial caspase activation factor in tumor cells treated with tumor necrosis factor. Thus, we have identified a novel class of compounds that inhibits apoptosis by blocking the activation of the initiator caspase 9 by directly inhibiting the formation of the apoptosome complex. This mechanism of action is different from that employed by the widely used tetrapeptide inhibitors of caspases or known endogenous apoptosis inhibitors, such as Bcl-2 and IAPs. Thus, these compounds provide a novel specific tool to investigate the role of the apoptosome in mitochondrion-dependent death paradigms.

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11

Potokar, Maja, Marko Kreft, Helena H. Chowdhury, Nina Vardjan, and Robert Zorec. "Subcellular localization of Apaf-1 in apoptotic rat pituitary cells." American Journal of Physiology-Cell Physiology 290, no. 3 (2006): C672—C677. http://dx.doi.org/10.1152/ajpcell.00331.2005.

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A key step in the intrinsic apoptotic pathway is the assembly of the apoptosome complex. The apoptosome components are well known; however, the physiology of the assembly of the apoptosome complex at the cellular level is still poorly defined. The aim of this work was to study the subcellular distribution of the apoptosome scaffold protein apoptotic protease-activating factor 1 (Apaf-1) before and after triggering apoptosis in single somatotrophs. Somatotrophs are the subject of extensive pituitary tissue remodeling in different physiological situations in which the quality and the number of pituitary cells are determined by cell proliferation and apoptosis. We show herein that 2 h after triggering apoptosis with rotenone, Apaf-1 redistributed to the proximity of mitochondria. In addition, the degree of colocalization between Apaf-1 and fluorescently labeled caspase-9 significantly increased during the same period. Furthermore, we show herein for the first time in single cells that the colocalization between Apaf-1 and cytochrome c increases only transiently, indicating a transient interaction between cytochrome c and Apaf-1 during the activation of apoptosis in these cells.

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12

Ferraro, Elisabetta, Angela Pulicati, Maria Teresa Cencioni, et al. "Apoptosome-deficient Cells Lose Cytochrome c through Proteasomal Degradation but Survive by Autophagy-dependent Glycolysis." Molecular Biology of the Cell 19, no. 8 (2008): 3576–88. http://dx.doi.org/10.1091/mbc.e07-09-0858.

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Cytochrome c release from mitochondria promotes apoptosome formation and caspase activation. The question as to whether mitochondrial permeabilization kills cells via a caspase-independent pathway when caspase activation is prevented is still open. Here we report that proneural cells of embryonic origin, when induced to die but rescued by apoptosome inactivation are deprived of cytosolic cytochrome c through proteasomal degradation. We also show that, in this context, those cells keep generating ATP by glycolysis for a long period of time and that they keep their mitochondria in a depolarized state that can be reverted. Moreover, under these conditions, such apoptosome-deficient cells activate a Beclin 1–dependent autophagy pathway to sustain glycolytic-dependent ATP production. Our findings contribute to elucidating what the point-of-no-return in apoptosis is. They also help in clarifying the issue of survival of apoptosome-deficient proneural cells under stress conditions. Unraveling this issue could be highly relevant for pharmacological intervention and for therapies based on neural stem cell transfer in the treatment of neurological disorders.

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13

Fullstone, Gavin, Tabea L. Bauer, Cristiano Guttà, Manuela Salvucci, Jochen H. M. Prehn, and Markus Rehm. "The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer." Cell Death & Differentiation 27, no. 10 (2020): 2828–42. http://dx.doi.org/10.1038/s41418-020-0545-9.

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Abstract The execution phase of apoptosis is a critical process in programmed cell death in response to a multitude of cellular stresses. A crucial component of this pathway is the apoptosome, a platform for the activation of pro-caspase 9 (PC9). Recent findings have shown that autocleavage of PC9 to Caspase 9 (C9) p35/p12 not only permits XIAP-mediated C9 inhibition but also temporally shuts down apoptosome activity, forming a molecular timer. In order to delineate the combined contributions of XIAP and the apoptosome molecular timer to apoptosis execution we utilised a systems modelling approach. We demonstrate that cooperative recruitment of PC9 to the apoptosome, based on existing PC9-apoptosome interaction data, is important for efficient formation of PC9 homodimers, autocatalytic cleavage and dual regulation by XIAP and the molecular timer across biologically relevant PC9 and APAF1 concentrations. Screening physiologically relevant concentration ranges of apoptotic proteins, we discovered that the molecular timer can prevent apoptosis execution in specific scenarios after complete or partial mitochondrial outer membrane permeabilisation (MOMP). Furthermore, its ability to prevent apoptosis is intricately tied to a synergistic combination with XIAP. Finally, we demonstrate that simulations of these processes are prognostic of survival in stage III colorectal cancer and that the molecular timer may promote apoptosis resistance in a subset of patients. Based on our findings, we postulate that the physiological function of the molecular timer is to aid XIAP in the shutdown of caspase-mediated apoptosis execution. This shutdown potentially facilitates switching to pro-inflammatory caspase-independent responses subsequent to Bax/Bak pore formation.

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14

Li, Yini, Mengying Zhou, Qi Hu, et al. "Mechanistic insights into caspase-9 activation by the structure of the apoptosome holoenzyme." Proceedings of the National Academy of Sciences 114, no. 7 (2017): 1542–47. http://dx.doi.org/10.1073/pnas.1620626114.

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Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is indispensable for caspase-9 activation by together forming a holoenzyme. The molecular mechanism of caspase-9 activation remains largely enigmatic. Here, we report the cryoelectron microscopy (cryo-EM) structure of an apoptotic holoenzyme and structure-guided biochemical analyses. The caspase recruitment domains (CARDs) of Apaf-1 and caspase-9 assemble in two different ways: a 4:4 complex docks onto the central hub of the apoptosome, and a 2:1 complex binds the periphery of the central hub. The interface between the CARD complex and the central hub is required for caspase-9 activation within the holoenzyme. Unexpectedly, the CARD of free caspase-9 strongly inhibits its proteolytic activity. These structural and biochemical findings demonstrate that the apoptosome activates caspase-9 at least in part through sequestration of the inhibitory CARD domain.

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15

Lindholm, Dan, and Urmas Arumäe. "Cell differentiation." Journal of Cell Biology 167, no. 2 (2004): 193–95. http://dx.doi.org/10.1083/jcb.200409171.

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The molecular mechanisms by which differentiated cells combat cell death and injury have remained unclear. In the current issue, it has been shown in neurons that cell differentiation is accompanied by a decrease in Apaf-1 and the activity of the apoptosome with an increased ability of the inhibitor of apoptosis proteins (IAPs) to sustain survival (Wright et al., 2004). These results, together with earlier ones, deepen our understanding of how cell death and the apoptosome are regulated during differentiation and in tumor cells.

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16

Steller, Hermann. "Staying alive: apoptosome feedback inhibition." Nature Cell Biology 10, no. 12 (2008): 1387–88. http://dx.doi.org/10.1038/ncb1208-1387.

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17

Belmokhtar, Chafké Ahmed, Josette Hillion, Charles Dudognon, et al. "Apoptosome-independent Pathway for Apoptosis." Journal of Biological Chemistry 278, no. 32 (2003): 29571–80. http://dx.doi.org/10.1074/jbc.m302924200.

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18

Hajra, K. M., and J. R. Liu. "Apoptosome dysfunction in human cancer." Apoptosis 9, no. 6 (2004): 691–704. http://dx.doi.org/10.1023/b:appt.0000045786.98031.1d.

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19

Shi, Yigong. "Mechanical aspects of apoptosome assembly." Current Opinion in Cell Biology 18, no. 6 (2006): 677–84. http://dx.doi.org/10.1016/j.ceb.2006.09.006.

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20

Teng, Xinchen, and J. Marie Hardwick. "The Apoptosome at High Resolution." Cell 141, no. 3 (2010): 402–4. http://dx.doi.org/10.1016/j.cell.2010.04.015.

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21

Cagnol, Sébastien, Anna Mansour, Ellen Van Obberghen-Schilling, and Jean-Claude Chambard. "Raf-1 Activation Prevents Caspase 9 Processing Downstream of Apoptosome Formation." Journal of Signal Transduction 2011 (October 14, 2011): 1–12. http://dx.doi.org/10.1155/2011/834948.

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In many cell types, growth factor removal induces the release of cytochrome-c from mitochondria that leads to activation of caspase-9 in the apoptosome complex. Here, we show that sustained stimulation of the Raf-1/MAPK1,3 pathway prevents caspase-9 activation induced by serum depletion in CCL39/Raf-1:ER fibroblasts. The protective effect mediated by Raf-1 is sensitive to MEK inhibition that is sufficient to induce caspase-9 cleavage in exponentially growing cells. Raf-1 activation does not inhibit the release of cytochrome-c from mitochondria while preventing caspase-9 activation. Gel filtration chromatography analysis of apoptosome formation in cells shows that Raf-1/MAPK1,3 activation does not interfere with APAF-1 oligomerization and recruitment of caspase 9. Raf-1-mediated caspase-9 inhibition is sensitive to emetine, indicating that the protective mechanism requires protein synthesis. However, the Raf/MAPK1,3 pathway does not regulate XIAP. Taken together, these results indicate that the Raf-1/MAPK1,3 pathway controls an apoptosis regulator that prevents caspase-9 activation in the apoptosome complex.

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22

Gyrd-Hansen, Mads, Thomas Farkas, Nicole Fehrenbacher, et al. "Apoptosome-Independent Activation of the Lysosomal Cell Death Pathway byCaspase-9." Molecular and Cellular Biology 26, no. 21 (2006): 7880–91. http://dx.doi.org/10.1128/mcb.00716-06.

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ABSTRACT The apoptosome, a heptameric complex of Apaf-1, cytochrome c, and caspase-9, has been considered indispensable for the activation of caspase-9 during apoptosis. By using a large panel of genetically modified murine embryonic fibroblasts, we show here that, in response to tumor necrosis factor (TNF), caspase-8 cleaves and activates caspase-9 in an apoptosome-independent manner. Interestingly, caspase-8-cleaved caspase-9 induced lysosomal membrane permeabilization but failed to activate the effector caspases whereas apoptosome-dependent activation of caspase-9 could trigger both events. Consistent with the ability of TNF to activate the intrinsic apoptosis pathway and the caspase-9-dependent lysosomal cell death pathway in parallel, their individual inhibition conferred only a modest delay in TNF-induced cell death whereas simultaneous inhibition of both pathways was required to achieve protection comparable to that observed in caspase-9-deficient cells. Taken together, the findings indicate that caspase-9 plays a dual role in cell death signaling, as an activator of effector caspases and lysosomal membrane permeabilization.

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23

Qi, Hong, Yu Jiang, Zhiyong Yin, Ke Jiang, Linxi Li, and Jianwei Shuai. "Optimal pathways for the assembly of the Apaf-1·cytochromeccomplex into apoptosome." Physical Chemistry Chemical Physics 20, no. 3 (2018): 1964–73. http://dx.doi.org/10.1039/c7cp06726g.

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24

Dorstyn, Loretta, Stuart Read, Dimitrios Cakouros, Jun R. Huh, Bruce A. Hay, and Sharad Kumar. "The role of cytochrome c in caspase activation in Drosophila melanogaster cells." Journal of Cell Biology 156, no. 6 (2002): 1089–98. http://dx.doi.org/10.1083/jcb.200111107.

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The release of cytochrome c from mitochondria is necessary for the formation of the Apaf-1 apoptosome and subsequent activation of caspase-9 in mammalian cells. However, the role of cytochrome c in caspase activation in Drosophila cells is not well understood. We demonstrate here that cytochrome c remains associated with mitochondria during apoptosis of Drosophila cells and that the initiator caspase DRONC and effector caspase DRICE are activated after various death stimuli without any significant release of cytochrome c in the cytosol. Ectopic expression of the proapoptotic Bcl-2 protein, DEBCL, also fails to show any cytochrome c release from mitochondria. A significant proportion of cellular DRONC and DRICE appears to localize near mitochondria, suggesting that an apoptosome may form in the vicinity of mitochondria in the absence of cytochrome c release. In vitro, DRONC was recruited to a &gt;700-kD complex, similar to the mammalian apoptosome in cell extracts supplemented with cytochrome c and dATP. These results suggest that caspase activation in insects follows a more primitive mechanism that may be the precursor to the caspase activation pathways in mammals.

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Yuan, Shujun, and Christopher W. Akey. "Apoptosome Structure, Assembly, and Procaspase Activation." Structure 21, no. 4 (2013): 501–15. http://dx.doi.org/10.1016/j.str.2013.02.024.

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Wu, Chu-Chiao, and Shawn B. Bratton. "DARK Apoptosome Secrets Come to Light." Structure 19, no. 1 (2011): 4–6. http://dx.doi.org/10.1016/j.str.2010.12.009.

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Acehan, Devrim, Xuejun Jiang, David Gene Morgan, John E. Heuser, Xiaodong Wang, and Christopher W. Akey. "Three-Dimensional Structure of the Apoptosome." Molecular Cell 9, no. 2 (2002): 423–32. http://dx.doi.org/10.1016/s1097-2765(02)00442-2.

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28

Adrain, C., and S. J. Martin. "Apoptosis: Calling Time on Apoptosome Activity." Science Signaling 2, no. 91 (2009): pe62. http://dx.doi.org/10.1126/scisignal.291pe62.

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Dorstyn, L., and S. Kumar. "A cytochrome c-free fly apoptosome." Cell Death & Differentiation 13, no. 7 (2006): 1049–51. http://dx.doi.org/10.1038/sj.cdd.4401918.

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Ledgerwood, E. C., and I. M. Morison. "Targeting the Apoptosome for Cancer Therapy." Clinical Cancer Research 15, no. 2 (2009): 420–24. http://dx.doi.org/10.1158/1078-0432.ccr-08-1172.

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Huber, Kristen L., Banyuhay P. Serrano, and Jeanne A. Hardy. "Caspase-9 CARD : core domain interactions require a properly formed active site." Biochemical Journal 475, no. 6 (2018): 1177–96. http://dx.doi.org/10.1042/bcj20170913.

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Caspase-9 is a critical factor in the initiation of apoptosis and as a result is tightly regulated by many mechanisms. Caspase-9 contains a Caspase Activation and Recruitment Domain (CARD), which enables caspase-9 to form a tight interaction with the apoptosome, a heptameric activating platform. The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site. The active sites of caspases are composed of four extremely mobile loops. When the active-site loops are not properly ordered, the CARD and core domains of caspase-9 do not interact and behave independently, like loosely tethered beads. When the active-site loop bundle is properly ordered, the CARD domain interacts with the catalytic core, forming a single folding unit. Taken together, these findings provide mechanistic insights into a new level of caspase-9 regulation, prompting speculation that the CARD may also play a role in the recruitment or recognition of substrate.

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ZECH, Birgit, Roman KÖHL, Andreas von KNETHEN, and Bernhard BRÜNE. "Nitric oxide donors inhibit formation of the Apaf-1/caspase-9 apoptosome and activation of caspases." Biochemical Journal 371, no. 3 (2003): 1055–64. http://dx.doi.org/10.1042/bj20021720.

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Caspases are critical for the initiation and execution of apoptosis. Nitric oxide (NO) or derived species can prevent programmed cell death in several cell types, reportedly through S-nitrosation and inactivation of active caspases. Although we find that S-nitrosation of caspases can occur in vitro, our study questions whether this post-translational modification is solely responsible for NO-mediated inhibition of apoptosis. Indeed, using Jurkat cells as a model system, we demonstrate that NO donors block Fas- and etoposide-induced caspase activation and apoptosis (downstream of mitochondrial membrane depolarization) and cytochrome c release. However, caspase activity was not restored by the strong reducing agent dithiothreitol, as predicted for S-nitrosation reactions, thereby excluding active-site-thiol modification of caspases as the only anti-apoptotic mechanism of NO donors in cells. Rather, we observed that processing of procaspases-9, −3 and −8 was decreased due to ineffective formation of the Apaf-1/caspase-9 apoptosome. Gel-filtration and in vitro binding assays indicated that NO donors inhibit correct assembly of Apaf-1 into an active approx. 700 kDa apoptosome complex, and markedly attenuate caspase-recruitment domain (CARD)–CARD interactions between Apaf-1 and procaspase-9. Therefore we suggest that NO or a metabolite acts directly at the level of the apoptosome and inhibits the sequential activation of caspases-9, −3 and −8, which are required for both stress- and receptor-induced death in cells that use the mitochondrial subroute of cell demise.

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Pop, Cristina, John Timmer, Sabina Sperandio, and Guy S. Salvesen. "The Apoptosome Activates Caspase-9 by Dimerization." Molecular Cell 22, no. 2 (2006): 269–75. http://dx.doi.org/10.1016/j.molcel.2006.03.009.

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Riedl, Stefan J., and Guy S. Salvesen. "The apoptosome: signalling platform of cell death." Nature Reviews Molecular Cell Biology 8, no. 5 (2007): 405–13. http://dx.doi.org/10.1038/nrm2153.

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Dorstyn, Loretta, Christopher W. Akey, and Sharad Kumar. "New insights into apoptosome structure and function." Cell Death & Differentiation 25, no. 7 (2018): 1194–208. http://dx.doi.org/10.1038/s41418-017-0025-z.

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Gholami, Leila, Elham Badrlou, Naghme Nazer, et al. "Expression of apoptosome-related genes in periodontitis." Gene Reports 23 (June 2021): 101029. http://dx.doi.org/10.1016/j.genrep.2021.101029.

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Oladzad, Azarakhsh, Maryam Nikkhah, and Saman Hosseinkhani. "Optimization of Experimental Variables Influencing Apoptosome Biosensor in HEK293T Cells." Sensors 20, no. 6 (2020): 1782. http://dx.doi.org/10.3390/s20061782.

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The apoptotic protease-activating factor 1 (Apaf-1) split luciferase biosensor has been used as a biological tool for the detection of early stage of apoptosis. The effect of doxorubicin in a cell-based assay and the addition of cytochrome c and ATP in a cell-free system have been used to test the functionality of the reporter for the detection of apoptosome formation. Here, our data established a drug- and cytochrome c/ATP-independent way of apoptosis induction relying on the expression of the biosensor itself to induce formation of apoptosome. Overexpression of Apaf-1 constructs led to increased split luciferase activity and caspase-3 activity in the absence of any drug treatment. Caspase-3 activity was significantly inhibited when caspase-9DN was co-overexpressed, while the activity of the Apaf1 biosensor was significantly increased. Our results show that the Apaf-1 biosensor does not detect etoposide-induced apoptosis.

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Kiang, Juliann G., Phillip D. Bowman, Xinyue Lu, et al. "Geldanamycin inhibits hemorrhage-induced increases in caspase-3 activity: role of inducible nitric oxide synthase." Journal of Applied Physiology 103, no. 3 (2007): 1045–55. http://dx.doi.org/10.1152/japplphysiol.00100.2007.

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Hemorrhage has been shown to increase inducible nitric oxide synthase (iNOS) and deplete ATP levels in tissues and geldanamycin limits both processes. Moreover, it is evident that inhibition of iNOS reduces caspase-3 and increases survival. Thus we sought to identify the molecular events responsible for the beneficial effect of geldanamycin. Hemorrhage in mice significantly increased caspase-3 activity and protein while treatment with geldanamycin significantly limited these increases. Similarly, geldanamycin inhibited increases in proteins forming the apoptosome (a complex of caspase-9, cytochrome c, and Apaf-1). Modulation of the expression of iNOS by iNOS gene transfection or siRNA treatment demonstrated that the level of iNOS correlates with caspase-3 activity. Our data indicate that geldanamycin limits caspase-3 expression and protects from organ injury by suppressing iNOS expression and apoptosome formation. Geldanamycin, therefore, may prove useful as an adjuvant in fluids used to treat patients suffering blood loss.

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Wright, Kevin M., Michael W. Linhoff, Patrick Ryan Potts, and Mohanish Deshmukh. "Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis." Journal of Cell Biology 167, no. 2 (2004): 303–13. http://dx.doi.org/10.1083/jcb.200406073.

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Despite the potential of the inhibitor of apoptosis proteins (IAPs) to block cytochrome c–dependent caspase activation, the critical function of IAPs in regulating mammalian apoptosis remains unclear. We report that the ability of endogenous IAPs to effectively regulate caspase activation depends on the differentiation state of the cell. Despite being expressed at equivalent levels, endogenous IAPs afforded no protection against cytochrome c–induced apoptosis in naïve pheochromocytoma (PC12) cells, but were remarkably effective in doing so in neuronally differentiated cells. Neuronal differentiation was also accompanied with a marked reduction in Apaf-1, resulting in a significant decrease in apoptosome activity. Importantly, this decrease in Apaf-1 protein was directly linked to the increased ability of IAPs to stringently regulate apoptosis in neuronally differentiated PC12 and primary cells. These data illustrate specifically how the apoptotic pathway acquires increased regulation with cellular differentiation, and are the first to show that IAP function and apoptosome activity are coupled in cells.

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Wang, Li, Qi Qiao, and Hao Wu. "Understanding CARD Tricks in Apoptosomes." Structure 25, no. 4 (2017): 575–77. http://dx.doi.org/10.1016/j.str.2017.03.013.

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Adams, Jerry M., and Suzanne Cory. "Apoptosomes: engines for caspase activation." Current Opinion in Cell Biology 14, no. 6 (2002): 715–20. http://dx.doi.org/10.1016/s0955-0674(02)00381-2.

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Yuan, Shujun, Xinchao Yu, Maya Topf, Steven J. Ludtke, Xiaodong Wang, and Christopher W. Akey. "Structure of an Apoptosome-Procaspase-9 CARD Complex." Structure 18, no. 5 (2010): 571–83. http://dx.doi.org/10.1016/j.str.2010.04.001.

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Bratton, S. B., and G. S. Salvesen. "Regulation of the Apaf-1-caspase-9 apoptosome." Journal of Cell Science 123, no. 19 (2010): 3209–14. http://dx.doi.org/10.1242/jcs.073643.

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D'Brot, A., P. Chen, M. Vaishnav, S. Yuan, C. W. Akey, and J. M. Abrams. "Tango7 directs cellular remodeling by the Drosophila apoptosome." Genes & Development 27, no. 15 (2013): 1650–55. http://dx.doi.org/10.1101/gad.219287.113.

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Park, Sang Eun, Nam Deuk Kim, and Young Hyun Yoo. "Acetylcholinesterase Plays a Pivotal Role in Apoptosome Formation." Cancer Research 64, no. 8 (2004): 2652–55. http://dx.doi.org/10.1158/0008-5472.can-04-0649.

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Shapiro, Peter J., Hans H. Hsu, Heekyung Jung, Edith S. Robbins, and Hyung Don Ryoo. "Regulation of the Drosophila apoptosome through feedback inhibition." Nature Cell Biology 10, no. 12 (2008): 1440–46. http://dx.doi.org/10.1038/ncb1803.

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Wu, Chu-Chiao, and Shawn B. Bratton. "Caspase-9 swings both ways in the apoptosome." Molecular & Cellular Oncology 4, no. 2 (2017): e1281865. http://dx.doi.org/10.1080/23723556.2017.1281865.

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davoodi, jamshid, Sanaz Naderi, Mahboobeh Kheikhah, Najmeh Ajili, Faezeh Attaran, and Somaye Sadeghzadeh. "Destabilizing Effect of Caspase-9 Association with Apoptosome." Biophysical Journal 110, no. 3 (2016): 218a. http://dx.doi.org/10.1016/j.bpj.2015.11.1209.

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Read, Stuart H., Belinda C. Baliga, Paul G. Ekert, David L. Vaux, and Sharad Kumar. "A novel Apaf-1–independent putative caspase-2 activation complex." Journal of Cell Biology 159, no. 5 (2002): 739–45. http://dx.doi.org/10.1083/jcb.200209004.

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CVaspase activation is a key event in apoptosis execution. In stress-induced apoptosis, the mitochondrial pathway of caspase activation is believed to be of central importance. In this pathway, cytochrome c released from mitochondria facilitates the formation of an Apaf-1 apoptosome that recruits and activates caspase-9. Recent data indicate that in some cells caspase-9 may not be the initiator caspase in stress-mediated apoptosis because caspase-2 is required upstream of mitochondria for the release of cytochrome c and other apoptogenic factors. To determine how caspase-2 is activated, we have studied the formation of a complex that mediates caspase-2 activation. Using gel filtration analysis of cell lysates, we show that caspase-2 is spontaneously recruited to a large protein complex independent of cytochrome c and Apaf-1 and that recruitment of caspase-2 to this complex is sufficient to mediate its activation. Using substrate-binding assays, we also provide the first evidence that caspase-2 activation may occur without processing of the precursor molecule. Our data are consistent with a model where caspase-2 activation occurs by oligomerization, independent of the Apaf-1 apoptosome.

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Kiang, Juliann G., Russell M. Peckham, Leah E. Duke, Tomoharu Shimizu, Irshad H. Chaudry, and George C. Tsokos. "Androstenediol inhibits the trauma-hemorrhage-induced increase in caspase-3 by downregulating the inducible nitric oxide synthase pathway." Journal of Applied Physiology 102, no. 3 (2007): 933–41. http://dx.doi.org/10.1152/japplphysiol.00919.2006.

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Soft tissue trauma and hemorrhage (T-H) diminishes various aspects of liver function, while it increases hepatic nitrate/nitrite, inducible nitric oxide synthase (iNOS), and endothelin-1 levels. Treatment with androstenediol (AED) inhibits the T-H-induced alterations of the above parameters. We sought to identify the molecular events underlying the beneficial effect of AED. Exposure of rats to T-H significantly increased the caspase-3 activity and protein, whereas treatment with AED significantly limited these increases. AED treatment also suppressed the T-H-induced increase in iNOS by effectively altering the levels of key transcription factors involved in the regulation of iNOS expression. Immunoprecipitation and immunoblotting analyses indicate that T-H increased apoptosome formation, and AED treatment significantly decreased it. Modulating the iNOS protein by transfecting cells with iNOS gene or small interfering RNA further confirmed the correlation between iNOS and caspase-3. Our data indicate that AED limits caspase-3 expression by suppressing the expression of transcription factors involved in the production of iNOS, resulting in decreased apoptosome. AED can potentially be a useful adjuvant for limiting liver apoptosis following T-H shock.

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