Caspases: cellular demolition experts

2001 ◽  
Vol 29 (6) ◽  
pp. 696-702 ◽  
Author(s):  
E. M. Creagh ◽  
S. J. Martin
Keyword(s):  
Cytochrome C ◽  
Limited Proteolysis ◽  
Cysteine Proteases ◽  
Caspase Activation ◽  
Caspase Family ◽  
Hierarchical Nature ◽  
Caspase Cascade ◽  
Cellular Stresses ◽  
Pro Inflammatory Cytokines

Apoptosis is co-ordinated by a family of cysteine proteases, the caspases, that dismantle the cell by targeting a panoply of proteins for limited proteolysis. The mammalian caspase family contains 14 members, a subset of which participates in apoptosis, with the remainder likely to be involved in the processing of pro-inflammatory cytokines. Apical caspase activation events are typically initiated by adaptor molecules that promote caspase aggregation and facilitate caspase auto-activation. In contrast, distal caspase activation events are controlled by caspases activated earlier in the cascade. Many cellular stresses provoke apoptosis by damaging mitochondria which results in the release of factors [such as cytochrome c and SMAC (second mitochondrial-derived activator of caspase)/Diablo] that trigger caspase activation and cell death. Here, we discuss the hierarchical nature of the caspase cascade that is triggered upon the release of mitochondrial cytochrome c into the cytoplasm, and the role of specific caspases within this cascade in targeting proteins for degradation. Finally, feedback amplification loops and important control points within the caspase cascade will be discussed.

Caspases and apoptosis

2002 ◽  
Vol 38 ◽  
pp. 9-19 ◽  
Author(s):  
Guy S Salvesen
Keyword(s):  
Cysteine Proteases ◽  
Signalling Pathways ◽  
Term Survival ◽  
Mature Adult ◽  
Intracellular Signalling Pathways ◽  
Adult Cell ◽  
Caspase Family ◽  
Cell Fragments ◽  
Pro Inflammatory Cytokines

The ability of metazoan cells to undergo programmed cell death is vital to both the precise development and long-term survival of the mature adult. Cell deaths that result from engagement of this programme end in apoptosis, the ordered dismantling of the cell that results in its 'silent' demise, in which packaged cell fragments are removed by phagocytosis. This co-ordinated demise is mediated by members of a family of cysteine proteases known as caspases, whose activation follows characteristic apoptotic stimuli, and whose substrates include many proteins, the limited cleavage of which causes the characteristic morphology of apoptosis. In vertebrates, a subset of caspases has evolved to participate in the activation of pro-inflammatory cytokines, and thus members of the caspase family participate in one of two very distinct intracellular signalling pathways.

scholarly journals The role of cytochrome c in caspase activation in Drosophila melanogaster cells

2002 ◽  
Vol 156 (6) ◽  
pp. 1089-1098 ◽  
Author(s):  
Loretta Dorstyn ◽  
Stuart Read ◽  
Dimitrios Cakouros ◽  
Jun R. Huh ◽  
Bruce A. Hay ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Mammalian Cells ◽  
Significant Proportion ◽  
Ectopic Expression ◽  
Caspase Activation ◽  
Cytochrome C Release ◽  
Cell Extracts ◽  
Effector Caspase ◽  
Drosophila Cells

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 >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.

Mechanisms of p53-dependent apoptosis

2001 ◽  
Vol 29 (6) ◽  
pp. 684-688 ◽  
Author(s):  
M. Schuler ◽  
D. R. Green
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Apoptotic Cell ◽  
Mitochondrial Outer Membrane ◽  
Caspase Activation ◽  
Caspase 9 ◽  
High Molecular Weight Complex ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Cellular Stresses ◽  
Induced Apoptosis

Cellular stresses, such as growth factor deprivation, DNA damage or oncogene expression, lead to stabilization and activation of the p53 tumour suppressor protein. Depending on the cellular context, this results in one of two different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Released cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9, which is activated following recruitment into the apoptosome. Active caspase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates caspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent the permeabilization of the outer mitochondrial membrane. The mechanism by which p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are transcriptional targets of p53. In addition, transcription-independent, pro-apoptotic activities of p53 have been described. The elucidation of the p53-dependent pathway, resulting in mitochondrial outer membrane permeabilization through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling the mechanism of stress-induced apoptosis.

scholarly journals Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4283-4290 ◽  
Author(s):  
Michael J. White ◽  
Simone M. Schoenwaelder ◽  
Emma C. Josefsson ◽  
Kate E. Jarman ◽  
Katya J. Henley ◽  
...  
Keyword(s):  
Steady State ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Platelet Production ◽  
Effector Caspase ◽  
Functional Regulation ◽  
Caspase Cascade ◽  
And Function

Abstract Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737–induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9−/− platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.

Spatially restricting caspase activation

2016 ◽  
Vol 9 (423) ◽  
pp. ec86-ec86
Author(s):  
Annalisa M. VanHook
Keyword(s):  
Short Form ◽  
Krebs Cycle ◽  
Cysteine Proteases ◽  
Specific Form ◽  
Mitochondrial Outer Membrane ◽  
S2 Cells ◽  
Caspase Activation ◽  
Link Type ◽  
Caspase Family ◽  
Caspase Regulation

In addition to executing programmed cell death, members of the caspase family of cysteine proteases also mediate the degradation of organelles and other cellular structures (see Minis and Steller). As the interconnected spermatids of Drosophilamelanogaster differentiate into mature sperm, they undergo a caspase-dependent process called “individualization,” during which the spermatids are separated and most of their cytoplasm and organelles are degraded. Aram etal. found that the β subunit of the ATP-specific form of succinyl-CoA synthetase (A-Sβ), a component of the Krebs cycle, restricts caspase activity to areas immediately around mitochondria. In yeast two-hybrid assays and coimmunoprecipitation experiments with extracts from cultured Drosophila S2 cells, A-Sβ interacted with Cul3T and Klhl10, two components of the testis-specific form of the Cullin-RING ubiquitin ligase (CRL3) complex that activates caspases. Expression of a testis-specific, long isoform of A-Sβ (A-SβT) increased during spermatid individualization and was required for caspase activation during individualization. A-SβT activated the CRL3 complex when the complex was reconstituted in S2 cells or ectopically expressed in the eye. Whereas the somatic, short form of A-Sβ (A-SβS) localizes to the mitochondrial matrix, A-SβT was present on the mitochondrial outer membrane and recruited Cul3 and Klhl10 to the mitochondrial surface. The authors mapped the domains of A-SβT that mediated binding to CRL3 and showed that A-SβT competed with an endogenous CRL3 inhibitor for binding to CRL3. Thus, A-SβT limits CRL3 activation to the mitochondrial surface, which in turn restricts caspase activation to this location to ensure that mitochondria are eliminated without triggering death of the spermatid.L. Aram, T. Braun, C. Braverman, Y. Kaplan, L. Ravid, S. Levin-Zaidman, E. Arama, A Krebs cycle component limits caspase activation rate through mitochondrial surface restriction of CRL activation. Dev.Cell37, 15–33 (2016). [PubMed]A. Minis, H. Steller, Krebs cycle moonlights in caspase regulation. Dev.Cell37, 1–2 (2016). [PubMed]

scholarly journals Caspase Family Proteases and Apoptosis

2005 ◽  
Vol 37 (11) ◽  
pp. 719-727 ◽  
Author(s):  
Ting-Jun Fan ◽  
Li-Hui Han ◽  
Ri-Shan Cong ◽  
Jin Liang
Keyword(s):  
Interleukin 1 ◽  
Critical Role ◽  
Cysteine Proteases ◽  
Inhibitor Of Apoptosis ◽  
Cascade System ◽  
Apoptosis Protein ◽  
Caspase Family ◽  
Caspase Cascade ◽  
And Function ◽  
Signal Cascades

Abstract Apoptosis, or programmed cell death, is an essential physiological process that plays a critical role in development and tissue homeostasis. The progress of apoptosis is regulated in an orderly way by a series of signal cascades under certain circumstances. The caspase-cascade system plays vital roles in the induction, transduction and amplification of intracellular apoptotic signals. Caspases, closely associated with apoptosis, are aspartate-specific cysteine proteases and members of the interleukin-1 β-converting enzyme family. The activation and function of caspases, involved in the delicate caspase-cascade system, are regulated by various kinds of molecules, such as the inhibitor of apoptosis protein, Bcl-2 family proteins, calpain, and Ca2+. Based on the latest research, the members of the caspase family, caspase-cascade system and caspase-regulating molecules involved in apoptosis are reviewed.

scholarly journals Ordering the Cytochrome c–initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9–dependent Manner

1999 ◽  
Vol 144 (2) ◽  
pp. 281-292 ◽  
Author(s):  
Elizabeth A. Slee ◽  
Mary T. Harte ◽  
Ruth M. Kluck ◽  
Beni B. Wolf ◽  
Carlos A. Casiano ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Dependent Manner ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Cell Extracts ◽  
Amplification Loop ◽  
Caspase Cascade ◽  
Inducible Activation

Exit of cytochrome c from mitochondria into the cytosol has been implicated as an important step in apoptosis. In the cytosol, cytochrome c binds to the CED-4 homologue, Apaf-1, thereby triggering Apaf-1–mediated activation of caspase-9. Caspase-9 is thought to propagate the death signal by triggering other caspase activation events, the details of which remain obscure. Here, we report that six additional caspases (caspases-2, -3, -6, -7, -8, and -10) are processed in cell-free extracts in response to cytochrome c, and that three others (caspases-1, -4, and -5) failed to be activated under the same conditions. In vitro association assays confirmed that caspase-9 selectively bound to Apaf-1, whereas caspases-1, -2, -3, -6, -7, -8, and -10 did not. Depletion of caspase-9 from cell extracts abrogated cytochrome c–inducible activation of caspases-2, -3, -6, -7, -8, and -10, suggesting that caspase-9 is required for all of these downstream caspase activation events. Immunodepletion of caspases-3, -6, and -7 from cell extracts enabled us to order the sequence of caspase activation events downstream of caspase-9 and reveal the presence of a branched caspase cascade. Caspase-3 is required for the activation of four other caspases (-2, -6, -8, and -10) in this pathway and also participates in a feedback amplification loop involving caspase-9.

Effect of pH, ionic charge, and osmolality on cytochromec-mediated caspase-3 activity

2001 ◽  
Vol 281 (4) ◽  
pp. C1196-C1204 ◽  
Author(s):  
Mark S. Segal ◽  
Elaine Beem
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Caspase Activation ◽  
Ionic Charge ◽  
Common Pathway ◽  
Vitro Assay ◽  
Free System ◽  
System A

Cytochrome c-mediated activation of caspase-3 is the final common pathway for most signals that induce apoptosis. Before release of cytochrome c from mitochondria, K+ and Cl− efflux and intracellular acidification must occur. We have utilized an in vitro assay to examine the role of pH, cations, anions, and uncharged molecules on the process of cytochrome c-mediated activation of procaspase-3. In this cell-free system, a pH above 7.4 severely suppressed the activation of procaspase-3 but not the activity of caspase-3. KCl, NaCl, and other salts all inhibited caspase activation, but uncharged molecules did not. Comparison of the inhibitory capacity of various salts suggests that the crucial element in causing suppression is the cation. The inhibition of alkaline pH could be overcome by increasing concentrations of cytochrome c, whereas the inhibition of ionic charge could not, suggesting that pH and salts affect the activation of caspase-3 by different mechanisms.

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