Gene name - Death-associated inhibitor of apoptosis 2
Synonyms - DRICE
Cytological map position - 99C1
Function - enzyme
Symbol - Drice
FlyBase ID: FBgn0019972
Genetic map position - 2-83
Classification - ICE-like protease (caspase) p20 and p10 domains
Cellular location - cytoplasmic
|Recent literature||Akagawa, H., Hara, Y., Togane, Y., Iwabuchi, K., Hiraoka, T. and Tsujimura, H. (2015). The role of the effector caspases drICE and dcp-1 for cell death and corpse clearance in the developing optic lobe in Drosophila. Dev Biol 404(2):61-75. PubMed ID: 26022392
In the developing Drosophila optic lobe, cell death occurs via apoptosis and in a distinctive spatio-temporal pattern of dying cell clusters. This study analyzed the role of effector caspases drICE and dcp-1 in optic lobe cell death and subsequent corpse clearance using mutants. Neurons in many clusters required either drICE or dcp-1 and each one was sufficient. This suggests that drICE and dcp-1 function in cell death redundantly. However, dying neurons in a few clusters strictly required drICE but not dcp-1, but required drICE and dcp-1 when drICE activity was reduced via hypomorphic mutation. In addition, analysis of the mutants suggests an important role of effecter caspases in corpse clearance. In both null and hypomorphic drICE mutants, greater number of TUNEL-positive cells were observed than in wild type, and many TUNEL-positive cells remained until later stages. Lysotracker staining showed that there was a defect in corpse clearance in these mutants. All the results suggested that drICE plays an important role in activating corpse clearance in dying cells, and that an additional function of effector caspases is required for the activation of corpse clearance as well as that for carrying out cell death.
|Wu, Y., Lindblad, J. L., Garnett, J., Kamber Kaya, H. E., Xu, D., Zhao, Y., Flores, E. R., Hardy, J. and Bergmann, A. (2015). Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila. Cell Death Differ . PubMed ID: 26542461
Caspases are the executioners of apoptosis. Although much is known about their physiological roles and structures, detailed analyses of missense mutations of caspases are lacking. As mutations within caspases are identified in various human diseases, the study of caspase mutants will help to elucidate how caspases interact with other components of the apoptosis pathway and how they may contribute to disease. DrICE is the major effector caspase in Drosophila required for developmental and stress-induced cell death. This study reports the isolation and characterization of six de novo drICE mutants, all of which carry point mutations affecting amino acids conserved among caspases in various species. These six mutants behave as recessive loss-of-function mutants in a homozygous condition. Surprisingly, however, two of the newly isolated drICE alleles are gain-of-function mutants in a heterozygous condition, although they are loss-of-function mutants homozygously. Interestingly, they only behave as gain-of-function mutants in the presence of an apoptotic signal. These two alleles carry missense mutations affecting conserved amino acids in close proximity to the catalytic cysteine residue. This result provides a significant exception to the expectation that mutations of conserved amino acids always abolish the pro-apoptotic activity of caspases.
|Ding, A. X., Sun, G., Argaw, Y. G., Wong, J. O., Easwaran, S. and Montell, D. J. (2016). CasExpress reveals widespread and diverse patterns of cell survival of caspase-3 activation during development. Elife 5. PubMed ID: 27058168
Caspase-3 carries out the executioner phase of apoptosis, however under special circumstances, cells can survive its activity. To document systematically where and when cells survive caspase-3 activation in vivo, a system, CasExpress, was designed that drives fluorescent protein expression, transiently or permanently, in cells that survive caspase-3 activation in Drosophila. Widespread survival was discovered of caspase-3 activity. Distinct spatial and temporal patterns emerged in different tissues. Some cells activated caspase-3 during their normal development in every cell and in every animal without evidence of apoptosis. In other tissues, such as the brain, expression was sporadic both temporally and spatially and overlapped with periods of apoptosis. In adults, reporter expression was evident in a large fraction of cells in most tissues of every animal; however the precise patterns varied. Inhibition of caspase activity in wing discs reduced wing size demonstrating functional significance. The implications of these patterns are discussed.
|Levayer, R., Dupont, C. and Moreno, E. (2016). Tissue crowding induces caspase-dependent competition for space. Curr Biol [Epub ahead of print]. PubMed ID: 26898471
Regulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied, the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density. Cell delamination was supposed to occur independently of caspase activation and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells. Studying the elimination of cells in the midline region of the Drosophila pupal notum, this study found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, this study confirmed that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers, that could promote tumor growth.
Cysteine proteases of the ICE/CED-3 family (caspases) are required for the execution of programmed cell death (PCD) in a wide range of multicellular organisms. Overexpression of Drosophila Ice is shown to sensitize Drosophila cells to apoptotic stimuli, and expression of an N-terminally truncated form of Ice rapidly induces apoptosis in Drosophila cells. Induction of apoptosis by rpr overexpression or by cycloheximide or etoposide treatment of Drosophila cells results in proteolytic processing of Ice. Ice is a cysteine protease that cleaves baculovirus p35 and Drosophila lamin DmO in vitro and Ice is expressed at all the stages of Drosophila development at which PCD can be induced. Drosophila caspases Dcp-1, Ice, Decay, and Damm lack long prodomains and are thus similar to downstream effector caspases in mammals. Taken together, these results strongly argue that Ice is an apoptotic caspase that acts downstream of rpr. Identification of Ice should facilitate the elucidation of upstream regulators and downstream targets of caspases by genetic screening (Fraser, 1997a).
Generation of functional sperm in all metazoan animals requires the elimination of most of the cytoplasm to generate a highly condensed, compact cell. The molecular and cellular mechanisms that drive this process are poorly understood. Evidence is provided that the elimination of the cytoplasm during terminal differentiation of elongated spermatids involves an apoptosis-like process. However, unlike 'regular' apoptosis, this process is restricted to the cytoplasmic compartment. The Effector caspase Ice is activated during Drosophila spermatogenesis and is necessary, along with other effector caspases, for the removal of cytoplasm and the generation of functional sperm. Other key proapoptotic proteins are also expressed and become upregulated during Drosophila spermatogenesis. These observations suggest that an apoptosome-like complex is assembled prior to individualization and is important for the removal of bulk cytoplasm from spermatids (Arama, 2003).
The final stage of spermatid terminal differentiation involves the removal of their bulk cytoplasm in a process known as spermatid individualization. Apoptotic proteins play an essential role during spermatid individualization in Drosophila. Several aspects of sperm terminal differentiation, including the activation of caspases, are reminiscent of apoptosis. Notably, caspase inhibitors prevent the removal of bulk cytoplasm in spermatids and block sperm maturation in vivo, causing male sterility. Loss-of-function mutations were identified in one of the two Drosophila cyt-c genes, Cyt-c-d; these mutations block caspase activation and subsequent spermatid terminal differentiation. Finally, a giant ubiquitin-conjugating enzyme, Bruce, is required to protect the sperm nucleus against hypercondensation and degeneration. These observations suggest that an apoptosis-like mechanism is required for spermatid differentiation in Drosophila (Arama, 2003).
Spermatogenesis in Drosophila takes place within individual units known as cysts. Each cyst contains 64 spermatids that remain initially connected after meiosis via cytoplasmic bridges and differentiate synchronously. During terminal differentiation, the round-shaped spermatids are transformed into thin, approximately 2 mm long spermatozoa with highly elongated, 'needle-shaped' nuclei. In the final stage of spermatogenesis, termed individualization, the cytoplasmic bridges are disconnected and most of the cytoplasm is expelled, leading to individual sperm. The individualization process involves the assembly of a cytoskeletal-membrane complex, referred to as the 'individualization complex' (IC), which contains actin as its major cytoskeletal component. The IC can be detected by staining with phalloidin, which binds to actin. In addition, lamin Dm0 leaves the vicinity of the nucleus and translocates as a component of the IC and thus can also be a useful marker of the IC. The IC is assembled at the nuclear end of the cyst and subsequently translocates caudally along the entire length of the spermatid bundle, expelling most of the cytoplasm in the process. The discarded cytoplasm accumulates in a membrane-enclosed structure, termed the waste bag (WB). The WBs eventually undergo fragmentation and subsequent degradation (Arama, 2003).
To investigate the possible occurrence of apoptosis during Drosophila sperm differentiation, live wild-type testes were stained with the vital dye acridine orange (AO), which specifically detects apoptotic cells. AO staining was observed in intact cystic bulges (CBs) and WBs. The staining of the CB and WB with AO in spermatids undergoing individualization suggests that the apoptotic program is activated in the late stages of sperm differentiation, and that CB and WB resemble apoptotic corpses without nuclei (Arama, 2003).
In mammals, mitochondria are an important organelle for the induction of apoptosis, and it has been shown that they can release several proapoptotic proteins into the cytosol in response to apoptotic stimuli. The best-studied case is the release of cytochrome c, which binds to and activates Apaf-1, which in turn leads to the activation of caspase-9. However, no comparable role of mitochondrial factors for caspase activation has yet been established in invertebrates. This study presents evidence that the cytochrome c encoded by the Cyt-c-d gene is required for the activation of the effector caspase Ice at the onset of spermatid individualization. Loss-of-function mutants for Cyt-c-d are homozygous viable but male-sterile. Significantly, these mutants are defective in Ice activation and fail to exclude the bulk cytoplasm, producing phenotypes virtually identical to the ones resulting from the application/expression of caspase inhibitors. This provides compelling evidence of a role for the Cyt-c-d gene for caspase activation during spermatogenesis in Drosophila. Interestingly, it has been suggested that only Cyt-c-p, but not cyt-c-d, functions in respiration. Consistent with an essential role of Cyt-c-p in respiration, a P element insertion into this locus results in recessive lethality. Likewise, targeted gene inactivation of the murine cytochrome c gene causes very early embryonic lethality, and this has precluded functional studies on the role of cytochrome c for caspase activation during normal development in mammals. It is proposed that the two cytochrome c genes in Drosophila fulfill distinct functions in respiration (cyt-c-p) and caspase activation/apoptosis (cyt-c-d). Previous arguments against a role of cytochrome c for caspase activation in Drosophila were largely based on the failure to detect release of cytochrome c from mitochondria. However, because cyt-c-d is expressed at much lower levels than cyt-c-p, it would be virtually impossible to detect the release of the relevant protein in the absence of highly specific antibodies. Furthermore, because cyt-c-d null flies are viable and, apart from male sterility, have no obvious anatomical defects, it is unlikely that this gene is broadly required for the activation of apoptosis. A complete block of apoptosis in Drosophila interferes with normal embryogenesis, and mutants with significantly reduced apoptosis can be viable but are phenotypically abnormal. Therefore, the loss of cyt-c-d function may affect and/or delay apoptosis in somatic tissues, the main function of this gene appears to be in caspase activation during spermatid differentiation (Arama, 2003).
Effector caspases, such as Ice, Dcp-1, and caspase-3, normally can cleave a variety of nuclear targets, including lamins, I-CAD, and PARP. Therefore, the sperm nucleus must be protected against this potentially lethal activity of Ice. The data indicate that Bruce, which encodes a giant E2 ubiquitin-conjugating enzyme, may exercise this function. Loss of Bruce function results in nuclear hypercondensation, degeneration, and male sterility, consistent with a role of dBruce to restrain or limit caspase activity. Interestingly, Bruce contains a BIR domain, a motif also found in IAPs. This suggests that Bruce may bind to either caspases or Reaper/Hid/Grim-like (RHG) proteins. Previous work has argued against RHG proteins as direct targets for Bruce. Therefore, it is attractive to speculate that Bruce functions by directly binding to and degrading caspases. Obviously, this proposed function would have to be spatially restricted during spermatogenesis, for example, by localizing Bruce to protected compartments, or by spatially limiting its E2 activity. An additional possibility is that Ice activation occurs only locally, in the affected compartment. Consistent with this idea, strong CM1 staining was only observed distal to the nuclei, in the cytoplasmic compartment that will be eliminated. One plausible mechanism for locally restricting Ice activation may be the local release of the 'minor' cytochrome c from mitochondria, which are known to undergo dramatic morphological changes only in the postindividualized portion of the cyst (Arama, 2003).
Terminal differentiation of sperm shares many morphological and biochemical features with apoptosis. However, rather than causing the death of the entire cell, in this case apoptotic proteins are used to specifically eliminate cytoplasmic components, thereby producing a highly specialized living cell. Interestingly, a similar phenomenon is observed in mammals. As in Drosophila, intracellular bridges between spermatids and the bulk of the spermatid cytoplasm need to be eliminated during mammalian spermatogenesis. In mammals, the cytoplasm collects in the residual body (RB), which is functionally homologous to the WB in Drosophila. Consistent with this idea, mammalian RBs display several features of apoptosis. Although a role of caspases for the removal of bulk cytoplasm during mammalian spermatogenesis remains to be established, preliminary data show that active caspase-3 is present in RBs in the testes of mice. Consequently, there are both anatomical and biochemical similarities between insects and mammals that warrant more detailed studies. This is not only of academic interest, since various types of caspase inhibitors are being considered as drugs for therapeutic purposes, and effects on human fertility have not been studied. Furthermore, the abnormal spermatozoa with residual cytoplasm resulting from caspase inhibition in Drosophila bear a striking resemblance to one of the most commonly seen abnormalities of human spermatozoa, known as cytoplasmic droplet sperm. Therefore, it is possible that defects in proper caspase activation may be responsible for this pathology, and further studies of apoptotic proteins may shed light on the etiology of some forms of human male infertility (Arama, 2003).
The Drosophila inhibitor of apoptosis protein DIAP1 exists in an auto-inhibited conformation, unable to suppress the effector caspase drICE. Auto-inhibition is disabled by caspase-mediated cleavage of DIAP1 after Asp20. The cleaved DIAP1 binds to mature drICE, inhibits its protease activity, and, presumably, also targets drICE for ubiquitylation. DIAP1-mediated suppression of drICE is effectively antagonized by the pro-apoptotic proteins Reaper, Hid, and Grim (RHG). Despite rigorous effort, the molecular mechanisms behind these observations are enigmatic. This study reports a 2.4 Å crystal structure of uncleaved DIAP1-BIR1, which reveals how the amino-terminal sequences recognize a conserved surface groove in BIR1 to achieve auto-inhibition, and a 3.5 Å crystal structure of active drICE bound to cleaved DIAP1-BIR1, which provides a structural explanation to DIAP1-mediated inhibition of drICE. These structures and associated biochemical analyses, together with published reports, define the molecular determinants that govern the interplay among DIAP1, drICE and the RHG proteins (Li, 2011).
The structural and biochemical information presented in this study gives rise to a model on the interplay of Dronc, drICE, DIAP1, and the RHG proteins. During homeostasis, DIAP1 targets the Dronc zymogen for ubiquitylation and presumably proteasome-mediated degradation. This regulation depends on the interaction between a peptide fragment of Dronc and the conserved groove on DIAP1-BIR2. DIAP1 exists in an auto-inhibited conformation. Caspase-mediated cleavage of DIAP1 after Asp20 disables auto-inhibition, allowing the resulting DIAP1 fragment to bind to and inhibit active drICE. During apoptosis, the RHG proteins use their N-terminal peptides to compete with drICE and Dronc for binding to the conserved peptide-binding grooves on the BIR1 and BIR2 domains, respectively. Such competition results in the release of drICE and Dronc from DIAP1. The freed Dronc zymogen is activated by the Dark apoptosome and the mature Dronc cleaves and activates drICE. In this regard, drICE, DIAP1 and the RHG proteins together provide a fail-safe mechanism to ensure appropriate drICE activation only under bona fide apoptotic conditions (Li, 2011).
The underpinning of this regulatory network is competition among multiple protein-protein interactions mediated by the conserved grooves of the BIR1 and BIR2 domains of DIAP1. Auto-inhibition of DIAP1-BIR1 is achieved by occupation of this groove by its own N-terminal sequence ASVV. The free peptide ASVV does not stably associate with BIR1; the covalent linkage facilitates the binding by increasing the local concentration of ASVV. This binding arrangement allows disabling of auto-inhibition upon cleavage of DIAP1 after Asp20. Inhibition of drICE by BIR1 requires occupation of this groove by the N-terminal sequences ALGS of drICE. Similar to ASVV, the free ALGS peptide exhibited no detectable binding to the BIR1 fragment. Three weak interfaces between BIR1 and drICE cooperate to yield a stable hetero-tetramer with a KD of approximately 1-2 microM. Removal of drICE inhibition by BIR1 depends on the interactions between RHG and the peptide-binding groove, with KD values of 0.12-0.76 microM. Endowing RHG with the strongest interactions ensures an apoptotic phenotype once the RHG proteins are activated in cells. It is acknowledged that the proposed model may be simplistic, as the network of protein-protein interactions and regulation is likely to be more complex in vivo. Nevertheless, the biophysical underpinnings described in this model are likely to have a role in various stages of apoptosis regulation (Li, 2011).
An IAP-binding motif, though not ostensibly abbreviated as IBM, was originally defined to contain four contiguous amino acids that resemble the Smac tetrapeptide AVPI. This structurally defined motif, with binding affinities of 0.1-1 microM, has stringent requirement for the first (P1), third (P3) and fourth (P4) amino acids. The P1 residue must be Ala, which binds to a small hydrophobic pocket on one end of the conserved groove on BIR domain. The P4 residue must be hydrophobic, preferably bulky, to occupy a greasy pocket on the other end of the groove. Deletion of P1 or P4 in a tetrapeptide results in abrogation of stable interaction with the BIR domain. The P3 residue is either Pro or Ala. Pro as P3, with its unique backbone configuration, optimizes simultaneous binding by both P1 and P4 residues for DIAP1-BIR2 or XIAP-BIR3. Ala as P3 can be better accommodated by DIAP1-BIR1 and XIAP-BIR2. In recent studies1, IBM was redefined to contain three contiguous amino acids, with P3 no longer restricted to Pro or Ala. Such tripeptides, ALG/AKG for drICE/Dcp1, or their longer variants, ALGS/AKGC for drICE/Dcp1, do not meet the structural criteria for IBM. Importantly, these peptides in isolation do not form a stable complex with any BIR domain. The definition of such motifs as IBMs insinuates the incorrect assumption that such free peptide motifs may stably interact with the BIR domain. This assumption, in turn, has engendered ample confusion in data interpretation in recent years (Li, 2011).
An IBM at the N-terminus of the caspase-9 small subunit recognizes a conserved surface groove on XIAP-BIR3; this interaction locks caspase-9 in the inhibited state. During apoptosis, Smac/Diablo uses a similar tetrapeptide motif to occupy the BIR3 groove, hence releasing caspase-9 and relieving XIAP-mediated inhibition. Caspase-3 or -7 is inhibited by an 18-residue peptide segment preceding the BIR2 domain of XIAP. Because both caspase-3 and drICE are inhibited directly at the active sites by XIAP and DIAP1, respectively, the overall appearance of the two BIR-caspase complexes is similar. It should be noted, however, that the essential interactions and key features are quite different. For example, caspase-3 or -7 can be inhibited by an isolated 18-residue peptide fused to GST; but the intact BIR1 domain of DIAP1 is absolutely required for drICE inhibition. The orientation of the BIR domain relative to the caspase is different by approximately 90 degrees between caspase-3/BIR2 and drICE/BIR1. Importantly, the peptide-binding groove of XIAP-BIR2 does not have an apparent role in the inhibition of caspase-3 and -7 (Li, 2011).
Using purified, recombinant proteins, this study showed that the BIR1 domain of DIAP1 only forms a stable complex with active drICE following caspase-mediated cleavage of DIAP1 after Asp20. The uncleaved DIAP1-BIR1 exhibited very weak binding to drICE. These observations contrast the report that both uncleaved and cleaved DIAP1-BIR1 bound to drICE similarly using coimmunoprecipitation. The cleaved DIAP1, but not the uncleaved DIAP1, potently inhibits the proteolytic activity of drICE towards both peptide and protein substrates. These observations unambiguously demonstrate that drICE sequestered by cleaved DIAP1 remains catalytically inactive. In fact, the conclusion that DIAP1-sequestered drICE was catalytically active, contradicted the biochemical observation that no protease activity was detectable towards peptide or protein substrate21. It is not uncommon for a substrate to be converted into a protease inhibitor upon cleavage, as exemplified by the pan-caspase inhibitor p35 (Li, 2011).
The key question is not whether BIR1 inhibits drICE, but why BIR1-sequestered drICE continues to exhibit proteolytic activity towards the uncleaved DIAP1. A time course analysis of DIAP1 cleavage shows that the protease activity of drICE was slowed down considerably over time, as the concentration of inhibitor -- cleaved DIAP1 -- increased. The level of drICE activity at the 15-minute time point was at least 6-fold higher than that at 90-minute point. This observation again illustrates that the cleaved DIAP1 is a bona fide inhibitor of drICE (Li, 2011).
Some of the contrasting claims about the regulation of drICE by DIAP1 might be attributable to the limitations of the investigative methods. Biochemical and biophysical investigations, employing homogeneous, recombinant proteins, usually provide mechanistic answers to questions that pertain to protein-protein interactions and enzyme activities. The caveat, however, is whether such observations are biologically relevant, and if yes, to what extent these findings are important. By contrast, investigation by cellular biochemistry, exemplified by coimmunoprecipitation, provides important clues to molecular mechanisms. For both approaches, caution must be exercised for the interpretation of results. Notably, in some cases, the contrasting claims can be reconciled by a complex system. For example, despite structural data demonstrating that the auto-inhibition of DIAP1 involves the binding of its N-terminal sequences to the BIR1 domain, it remains theoretically possible that additional interactions between the N- and C-terminal domains of DIAP1 may contribute to its auto-inhibition1. The best example is Apaf-1, whose auto-inhibition entails two elements: one by the C-terminal WD40 repeats and the other within the N-terminal half. Binding to cytochrome c relieves the auto-inhibition by the WD40 repeats31, and exchange of ADP for ATP defeats the auto-inhibition imposed by intra-domain interactions within the N-terminal-half (Li, 2011).
The suppression of cell death in Drosophila by p35 expression in vivo strongly indicates a role for caspases in the cell death machinery of Drosophila. To search for these caspases, a degenerate PCR-based strategy was used. A unique band of ~200 bp was obtained after performing PCR on a 4-8 h embryonic D. melanogaster cDNA library and this was used to probe the same cDNA library. The resulting full-length cDNA was sequenced and found to contain a single ORF, encoding a protein with 38.9% identity with human CPP32 and Mch2 and 30.4% with C. elegans CED-3. The predicted protein, Ice, contains all the residues required for catalysis by caspases. The catalytic cysteine (C211) sits in a QACQG pentapeptide, as is the case for certain mammalian caspases FLICE/MACH1 and Mch4. The predicted small subunit contains a region similar to the P4 specificity loop of human CPP32beta shown to be critical in determining its substrate specificity for an aspartic acid residue at the P4 position rather than a large hydrophobic residue and Ice might therefore be predicted to share such a specificity. CED-3 also contains this P4-specificity region and shares similar substrate specificity with CPP32beta, from which it is inferred that all three proteases, from widely divergent organisms, probably share similar substrate specificity. Ice also contains an unusual N-terminal region which contains 30.8% Ser and 28.2% Gly (S32-Y69). The only other IRP known to contain a similar sequence is CED-3, whose N-terminal (S132-G206) highly Ser-rich (36.5%) region is of unknown function. Drosophila caspases Dcp-1, Ice, Decay, and Damm lack long prodomains and are thus similar to downstream effector caspases in mammals. Given the current emerging picture in which the N-terminal prodomains of caspases couple these enzymes to upstream regulators, the conservation of such a motif may have functional significance. Moreover, CED-3 is processed at D221 which is immediately C-terminal to the Ser-rich region and, since Ice also has an aspartic acid residue (D80) at the immediate C-terminal end of its Ser-rich region, this suggests that D80 might be the Ice N-terminal processing site (Fraser, 1997a).
See Drosophila Death Caspase-1 for information on eukaryotic caspases
date revised: 8 August 2003
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