Executioner caspase-3 and caspase-7 are functionally distinct proteases

Walsh, J.; Cullen, Sean P.; Sheridan, Clare; Lüthi, Alexander U.; Gerner, Christopher; Martin, Séamus J.

doi:10.1073/pnas.0707715105

Cited by 507 publications

(413 citation statements)

References 18 publications

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“…Despite apparently overlapping substrate specificity, caspase-7 and caspase-3 have been shown to exhibit distinct subcellular distributions in mouse livers treated with anti-Fas antibody (Chandler et al 1998). More recent studies have supported distinct roles of these caspases in cellular breakdown during apoptosis (Walsh et al 2008). These findings are reinforced by a comparison of phenotypes from caspase-3 -/ -, caspase-7 -/ -, and double knockout mice (and MEFs), which suggests both separate and redundant roles for these caspases (Lakhani et al 2006).…”

Section: Caspase-7mentioning

confidence: 51%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

511

367

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Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death.

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Section: Caspase-7mentioning

confidence: 51%

Cellular Mechanisms Controlling Caspase Activation and Function

Parrish

Freel

Kornbluth

2013

Cold Spring Harbor Perspectives in Biology

511

367

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“…However, cleavage of XIAP was inhibited by both inhibitors as the cleavage is only mediated by caspase-3. Examination of the effects of the two inhibitors on the cleavage of p23, which may be a specific caspase-7 substrate, 30 showed that all z-VAD.fmk concentrations completely inhibited its cleavage, whereas only higher M-791 concentrations caused a slight inhibition (Figure 1i, compare lanes 3-5 with 4-9). Thus, these data further support the selectivity of M-791 as a specific inhibitor of caspase-3 activity.…”

Section: Resultsmentioning

confidence: 99%

Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

et al. 2009

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Caspases are a family of aspartate-specific cysteine proteases responsible for the biochemical and morphological changes that occur during the execution phase of apoptosis. The hierarchical ordering of caspases has been clearly established using dATPactivated cell lysates to model the intrinsic pathway induced by initial mitochondrial perturbation. In this model, caspase-9, the apical caspase, directly processes and activates the effector caspases, caspase-3 and -7, and then active caspase-3 but not caspase-7, processes caspase-2 and -6, and subsequently the activated caspase-6 processes caspase-8 and -10. To address the possibility that this model in vitro system might not reflect the precise ordering of caspases in intact cells, we have examined this possibility in cells induced to undergo apoptosis by activation of the intrinsic pathway. We have used caspase deficient cells, small interference RNA for caspase-6 and -7, and a specific caspase-3 inhibitor. In contrast to the earlier in vitro studies, we now show that in intact cells caspase-7 can also directly process and activate caspase-2 and -6. The processing of caspase-2 and -6 occurs within the cytoplasm and active caspase-6 is then responsible for both the processing of caspase-8 and the cleavage of caspase-6 substrates, including lamin A/C. Apoptosis, a major form of cell death used to remove unwanted or excess cells, is characterized by a plethora of morphological and biochemical changes resulting primarily from the activation of a family of cysteine proteases, which cleave their substrates at specific aspartate residues. 1-4 Two major apoptotic pathways have been described, the intrinsic pathway involving initial mitochondrial perturbation resulting from cellular stress or cytotoxic insults and the extrinsic pathway, which is triggered by the activation of death receptors of the TNF family. 5-7 Caspase-8 and -9, the apical caspases in the extrinsic and intrinsic pathways, possess a protein interaction prodomain, which result in their recruitment and subsequent activation within cellular complexes, namely the death-inducing signaling complex (DISC) and the Apaf-1 apoptosome, respectively, and the subsequent activation of effector caspases, such as caspase-3, -6 and -7. 5,[8][9][10] Caspases are synthesized as single-chain zymogens, containing an N-terminal prodomain, as well as large (B20 kDa) and small (B10 kDa) subunits, with the basic catalytic domain forming from a large and small subunits. 1,3,4 Caspase-2 also has a sizeable prodomain, but it is unclear whether it should be considered an initiator or an effector caspase. 3 Although caspase-2 has been proposed to act upstream of mitochondria and to be activated within the PIDDosome, it may also be activated downstream of caspase-3. 11-14 Using recombinant proteins, caspase-3, -8 and to a lesser extent caspase-7 can process caspase-2. 15 The physiological role of caspase-2 is not known and no marked phenotype is observed in caspase-2 À/À mice. Caspase-6 is generally considered to be an effector casp...

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“…Despite this apparent redundancy, these two capases have an overlapping but nonidentical substrate repertoire. For example, Rho kinase ROCK1, α-fodrin, and Rho-GDI are cleaved efficiently by both caspases (8,9). However, inhibitor of caspase-activated Dnase (ICAD) (9), the X-linked inhibitor of apoptosis protein (XIAP) (10), and initiator caspase-9 (11) are preferred by caspase-3, whereas Nogo-B (12), ataxin-7 (13), and the p23 cochaperone (9) are cleaved more efficiently by caspase-7.…”

mentioning

confidence: 99%

Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis

Boucher

Blais

Denault

2012

Proc. Natl. Acad. Sci. U.S.A.

110

103

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During apoptosis, hundreds of proteins are cleaved by caspases, most of them by the executioner caspase-3. However, caspase-7, which shares the same substrate primary sequence preference as caspase-3, is better at cleaving poly(ADP ribose) polymerase 1 (PARP) and Hsp90 cochaperone p23, despite a lower intrinsic activity. Here, we identified key lysine residues (K 38 KKK) within the N-terminal domain of caspase-7 as critical elements for the efficient proteolysis of these two substrates. Caspase-7's N-terminal domain binds PARP and improves its cleavage by a chimeric caspase-3 by ∼30-fold. Cellular expression of caspase-7 lacking the critical lysine residues resulted in less-efficient PARP and p23 cleavage compared with cells expressing the wild-type peptidase. We further showed, using a series of caspase chimeras, the positioning of p23 on the enzyme providing us with a mechanistic insight into the binding of the exosite. In summary, we have uncovered a role for the N-terminal domain (NTD) and the N-terminal peptide of caspase-7 in promoting key substrate proteolysis.caspase substrate | molecular recognition | enzymology A poptosis employs a family of cysteinyl peptidases, the caspases, to integrate and propagate various signals to cause cell demise. The latter step is governed by a subgroup of caspases named executioners that are responsible for the cleavage of a plethora of cellular proteins. The cleavage of some of these proteins provokes the associated hallmarks of apoptosis (1, 2). A survey of the published literature suggests that, among executioners, caspase-3 performs the bulk of the cleavage events. These data are in agreement with biochemical studies suggesting that this caspase is highly active and is present at the highest concentration among all caspases in most cells (3)(4)(5). For these reasons, caspase-3 supersedes other caspases in most biochemical readouts (4).Caspase-3 and -7 share 57% sequence identity throughout their catalytic domains. Additionally, they have the same substrate preference based on studies using peptide substrate libraries (6, 7). Despite this apparent redundancy, these two capases have an overlapping but nonidentical substrate repertoire. For example, Rho kinase ROCK1, α-fodrin, and Rho-GDI are cleaved efficiently by both caspases (8, 9). However, inhibitor of caspase-activated Dnase (ICAD) (9), the X-linked inhibitor of apoptosis protein (XIAP) (10), and initiator caspase-9 (11) are preferred by caspase-3, whereas Nogo-B (12), ataxin-7 (13), and the p23 cochaperone (9) are cleaved more efficiently by caspase-7. Poly(ADP ribose) polymerase 1 (PARP), the first caspase substrate identified (14), is a particularly interesting death substrate, and its cleavage is now recognized as a hallmark of apoptosis. PARP proteolysis is essential for an adequate energetic balance during apoptosis and protects against necrosis (15, 16). Previous work has suggested that caspase-7 is responsible for PARP inactivation during apoptosis (17), but no mechanism for such selectivity has been propos...

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Executioner caspase-3 and caspase-7 are functionally distinct proteases

Cited by 507 publications

References 18 publications

Cellular Mechanisms Controlling Caspase Activation and Function

Cellular Mechanisms Controlling Caspase Activation and Function

Ordering of caspases in cells undergoing apoptosis by the intrinsic pathway

Caspase-7 uses an exosite to promote poly(ADP ribose) polymerase 1 proteolysis

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