JXB Advance Access published online on February 13, 2008
Journal of Experimental Botany, doi:10.1093/jxb/erm352
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FOCUS REVIEW PAPER |
What happened to plant caspases?
1Faculty of Life Sciences, University of Manchester, 3.614 Stopford Building, Oxford Road, Manchester M13 9PT, UK
2UMR Plante-Microbe-Environnement, INRA 1088/CNRS 5184/U-Bourgogne, BP 86510, 21065 Dijon Cedex, France
* To whom correspondence should be addressed. E-mail: patrick.gallois{at}manchester.ac.uk
Received 20 November 2007; Revised 11 December 2007 Accepted 13 December 2007
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Abstract |
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Top
Abstract
IntroductionThe extent of conservation in the programmed cell death pathways that are activated in species belonging to different kingdoms is not clear. Caspases are key components of animal apoptosis; caspase activities are detected in both animal and plant cells. Yet, while animals have caspase genes, plants do not have orthologous sequences in their genomes. It is 10 years since the first caspase activity was reported in plants, and there are now at least eight caspase activities that have been measured in plant extracts using caspase substrates. Various caspase inhibitors can block many forms of plant programmed cell death, suggesting that caspase-like activities are required for completion of the process. Since plant metacaspases do not have caspase activities, a major challenge is to identify the plant proteases that are responsible for the caspase-like activities and to understand how they relate, if at all, to animal caspases. The protease vacuolar processing enzyme, a legumain, is responsible for the cleavage of caspase-1 synthetic substrate in plant extracts. Saspase, a serine protease, cleaves caspase-8 and some caspase-6 synthetic substrates. Possible scenarios that could explain why plants have caspase activities without caspases are discussed.
Key words: Caspase-like, metacaspases, plants, programmed cell death, protease
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Introduction |
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The extent of the conservation in the programmed cell death (PCD) pathways that occurs in species belonging to different kingdoms is not clear. At the cellular level, PCD in plants can be compared, in some instances, with animal apoptosis and, in other instances, with animal autophagic cell death (van Doorn and Woltering, 2004). Both these types of animal cell death can be caspase independent or caspase dependent. The apparent but limited similarity between animal PCD and plant PCD has stimulated research in plant caspases that started before the whole sequence of the Arabidopsis genome was known. Initial reports seemed to provide indirect evidence supporting the existence of caspase orthologues in plants, with several caspase-like activities detected in plant extracts, and mammalian caspase inhibitor studies which showed them to be required for PCD (Rotari et al., 2005). Biochemical data have accumulated using synthetic substrates designed for enzymatic assays with members of the three groups of caspases (cytokine processors, apoptotic initiators, and apoptotic effectors), which prefer either a hydrophobic, aliphatic, or aspartic acid residue, respectively in the P4 position of substrates (Thornberry et al., 1997; Nicholson, 1999; Wolf and Green, 1999). However, sequencing the Arabidopsis and later the rice genome proved the absence of orthologous caspase sequences in plants. Because of the absence of caspase genes in plants, the corresponding plant activities are referred to as caspase-like. In addition, referring to a specific caspase activity, for example caspase-3-like, is not helpful in a plant context. Caspase-like activities are therefore often referred to using the amino acid sequence of the substrate cleaved. For example, an activity against the substrate DEVD will be referred to as a DEVDase activity. It is now 10 years since the first published report of caspase activity in plants (del Pozo and Lam, 1998). This review is looking into the conundrum of detecting caspase-like activities in plants without the presence of true caspase genes.
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PCD and caspase-like activities in plants |
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Caspase-like activities have been detected in plants using mostly synthetic tetrapeptide substrates designed using the preferred cleavage site consensus of members of the mammalian caspase family. These substrates are not truly ‘caspase-specific’ and have overlapping specificities with various caspases and other proteases (Stennicke and Salvesen, 2000). It is therefore difficult to interpret caspase-like activity profiles in whole plant extracts. Additional data available in the literature such as pH optimum, NaCl tolerance, and partial purification suggest that there could be up to eight distinct caspase-like activities in plants. Most of these activities have been detected multiple times in various species and in various tissues or cell types (Table 1). YVADase and DEVDase have been the most studied, and both activities were detected in the majority of PCD situations, illustrating their ubiquity. Additional novel activities have been reported over the last few years because a greater variety of substrates has become commercially available. This is the case for VEIDase, IETDase, VKMDase, LEHDase, and LEVDase (Table 1). These activities have not been tested for in early studies so at present it is not possible to assess how widespread these activities are. The detection of caspase-like activities, which correlates with PCD induction, does not demonstrate in itself an involvement in the process. Proof that caspase-like activities are required for completion of PCD must be obtained using a caspase inhibitor corresponding to the substrate used. The use of the baculovirus protein p35, a pan caspase inhibitor, demonstrated this requirement by virtue of being effective at blocking cell death in several experimental systems: Agrobacterium tumefaciens-induced PCD using embryonic callus in maize (Hansen, 2000), Alternaria alternata f. sp. lycopersici AAL-toxin-induced cell death (Lincoln et al., 2002); hypersensitive response (HR) cell death in tobacco plants infected with Pseudomonas syringae pv. phaseolicola or tobacco mosaic virus (TMV) (del Pozo and Lam, 2003), and UV-induced PCD in Arabidopsis (Danon et al., 2004). Synthetic inhibitors designed to block caspase activities have also been used and supported similar conclusions. Most of these inhibitors are remarkably efficient at suppressing many types of plant cell death, with a few notable variations (Table 2). Acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) had no effect on the formation of necrotic lesions in tobacco induced by TMV, while acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-CHO) had an effect (Chichkova et al., 2004; Hatsugai et al., 2004). On the contrary, Ac-YVAD-CHO does not suppress cell death of pollen tubes in Papaver while Ac-DEVD-CHO does (Thomas and Franklin-Tong, 2004). Overall, caspase-like activities are involved in most PCD responses, suggesting that these activities are part of the core mechanism of plant PCD. A notable exception may be xylem development. The absence of cell death reduction in the presence of Ac-YVAD-CHO has been reported in the Zinnia xylem differentiation system (Fukuda, 1997) but not published in detail. In this context, a xylem study using the full range of caspase inhibitors available would prove very informative. In addition, it has been reported that HR induced by P. syringae pv. maculicola was not blocked when using either Ac-DEVD-CHO or Ac-YVAD-CHO (Krzymowska et al., 2007). These two cases illustrate the fact that there are plant PCD pathways that are caspase-like independent. The current challenge is to identify all the proteases responsible for the caspase-like activities detected and to fit them in a PCD pathway.
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The rise of metacaspases |
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Sequence and structural analysis using genome data revealed a greater diversity of caspase-related proteases than previously suspected. In particular, Uren et al. (2000) identified two families of predicted proteases that are more closely related to animal caspases than to other proteases. These two families were designated paracaspases and metacaspases. Paracaspases and caspases appear animal specific, whereas metacaspases are present in other eukaryotes including yeast, fungi, and plants. Metacaspases are separated in to type I and type II, based on sequence and structure similarity. A major role for metacaspases in plants PCD was put forward for four reasons (Aravind and Koonin, 2002): (i) a common origin with caspases; (ii) the absence of closer caspase homologues in plants; (iii) the proliferation of the genes coding for metacaspases in plant genomes as a mirror image of the proliferation of caspases in animal genomes; and (iv) the fusion of the type I plant metacaspases with a Zn-finger domain also present in LSD1, a regulator of the hypersensitive response in plants (Dietrich et al., 1997). For some time it was expected that plant metacaspases would have caspase-like activities.
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Metacaspases do not cleave caspase substrates |
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Early observations using cell extracts suggested that metacaspases could correspond to the caspase-like activities detected in plants, yeast, and fungi (Madeo et al., 2002; Suarez et al., 2004). However, four reports have now demonstrated that plant metacaspases are unable to cleave caspase substrates. Five recombinant metacaspases out of the nine Arabidopsis genes have been produced and all have Arg as the preferred amino acid in the P1 position in their tetrapeptide substrates in vitro (Vercammen et al., 2004; Watanabe and Lam, 2005; He et al., 2007). Bozhkov et al. (2005) also produced a recombinant metacaspase from pine and showed a preferred cleavage in vitro for EGR. More recently, Vercammen et al. (2006) used a peptide library and showed that recombinant Arabidopsis metacaspase-9 preferred the synthetic substrate VRPR. Very importantly, all these recombinant metacaspases do not cleave caspase substrates and their enzymatic activity is not inhibited by caspase inhibitors. In addition, extracts of Arabidopsis plants overexpressing metacaspase-8 have increased FRase activities and do not have increased caspase-like activities (He et al., 2007).
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Metacaspase-dependent or metacaspase-independent PCD? |
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Although metacaspases do not have caspase-like activities, several publications support a role for metacaspases in PCD. In plants, the down-regulation of a type II metacaspase suppresses PCD in the suspensor cells of an embryogenic culture of Picea abies (Suarez et al., 2004). PCD phenotypes in Arabidopsis have been less forthcoming, possibly due to gene redundancy as most of the nine metacaspase genes are expressed at various levels in various parts of the plant (He et al. 2007). Still single KO lines of metacaspase type II have a small but significant phenotype with a reduced cell death when challenged by the plant pathogen Botrytis (Van Baarlen et al., 2007). Metacaspase-8 is a member of the metacaspase gene family strongly up-regulated by UVC, H2O2, and methyl viologen (He et al. 2007), giving an opportunity to detect a KO phenotype during PCD triggered by these chemicals. Accordingly, metacaspase-8 KO lines showed a reduced cell death triggered by UVC or H2O2 in protoplasts. In addition, knockout seeds and seedlings had an increased tolerance to methyl viologen (He et al., 2007), a herbicide that induces PCD (Chen and Dickman, 2004).
Overexpression studies in Arabidopsis have yielded informative results. Vercammen et al. (2006) indicated that, in their study, Arabidopsis plants overproducing selected members of the metacaspase gene family had no obvious cell death-related phenotype. Arabidopsis lines overexpressing metacaspase-8 have no obvious developmental phenotypes (He et al., 2007). The viability of overexpressers could suggest a post-translational regulation of metacaspase activation. Members of the serpin family are good candidates for regulating enzymatic activity of metacaspase since a serpin has been shown to inhibit metacaspase-9 (Vercammen et al., 2006). In addition, S-nitrosylation in planta could be another regulation step as it has been shown to inhibit metacaspase-9 activation (Belenghi et al., 2007). It cannot be excluded, however, that metacaspases may not be directly involved in the regulation of cell death but rather, directly or indirectly, in signalling cascades leading to cell death. Still leaf discs from lines overexpressing metacaspase-8 showed increased ion leakage, a marker of PCD, when challenged by UVC or H2O2 (He et al., 2007). Protoplasts prepared from overexpressing seedlings had increased PCD when treated with UV or H2O2 (He et al., 2007). Crucially metacaspase-8 up-regulation is dependent on RCD1. RCD1 is thought to interact with transcription factors and regulate some of the oxidative stress response (Belles-Boix et al., 2000). Whether RCD1 is required directly or indirectly for metacaspase-8 expression is not known. It remains that an RCD1 requirement for expression places metacaspase-8 in an oxidative stress pathway leading to PCD, illustrating specialization in a plant metacaspase family. Because the single yeast metacaspase is required for PCD induced by H2O2 (Madeo et al., 2002), metacaspase-8 may be part of a PCD pathway activated by oxidative stress that is evolutionarily conserved between plants and yeast.
In plants, where metacaspases are encoded by large gene families, it may be that some members of the family are involved in the regulation of PCD and some may be involved in other processes. In addition, different PCD pathways activated in plants may be either metacaspase-dependent or metacaspase-independent. In support of this hypothesis, a yeast metacaspase (YCA1) KO is able to survive conditions that induce PCD in the wild-type, for example H2O2 or acetic acid (Madeo et al., 2002), virus infection (Ivanovska and Hardwick, 2005), and hyperosmotic stress (Silva et al., 2005). By contrast, the yeast metacaspase is not required for PCD during mating (Zhang et al., 2006), triggered by ammonia (Vachova and Palkova, 2005), or induced by Bax expression (Guscetti et al., 2005). Intriguingly, a study using a double metacaspase KO strain in Aspergillus fumigatus found metacaspases required only for one marker of cell death, phosphatidylserine exposure, but not for two other markers—activation of caspase-like activities or loss of viability (Richie et al., 2007).
Finally, it has been suggested that metacaspases may not be directly involved in PCD (Vercammen et al., 2007), in which case the only commonality between metacaspases and caspases may be a name. Metacaspases in Trypanosoma brucei were suggested to play a role in cell proliferation and mitochondria biogenesis (Szallies et al., 2002). Using the same organism, no support was found for a metacaspase role in PCD using a range of stresses (Helms et al., 2006). Identifying some of the metacaspase in vivo substrates will be crucial to the understanding of their in vivo function.
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The protease vacuolar processing enzyme cleaves caspase-1 substrate (YVAD) |
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The plant vacuolar processing enzyme (VPE) had initially been characterized as active against the substrates ESEN and AAN, and as being involved in various protein maturation processes in seed or leaf (Yamada et al., 2005). Unexpectedly, virus-induced gene silencing of VPE in Nicotiana benthamiana demonstrated that VPE had YVADase activity, a caspase-1 like activity, and was required for TMV-induced cell death (Hatsugai et al., 2004). Subsequent KO experiments in Arabidopsis have shown VPE to be required in two more cell death systems: fumonisin-induced cell death (Kuroyanagi et al., 2005) and developmental cell death in seed integuments (Nakaune et al., 2005).
The YVADase activity was formally confirmed in enzymatic assays using recombinant 
-VPE produced in insect cells. Recombinant -VPE was shown to be active against both ESEN (VPE substrate) and YVAD (caspase-1 substrate) (Kuroyanagi et al., 2005). Arabidopsis has four VPE genes, 
-VPE, β-VPE, -VPE, and 
-VPE. A quadruple-KO mutant had no detected VPE or YVADase activity, strongly suggesting that there was no other proteases with a similar activity in plants (Kuroyanagi et al., 2005). Experiments comparing a -VPE KO with the wild type using the biotinylated inhibitor biotin-YVAD-fmk to detect caspase-1 activity suggested that -VPE had caspase-1 activity too (Nakaune et al., 2005). Interestingly, recombinant -VPE is inactive against a DEVD substrate (Kuroyanagi et al., 2005), although the corresponding inhibitor Ac-DEVD-fmk is able to inhibit VPE activity (AAN) in plant extracts (Rojo et al., 2004; Nakaune et al., 2005). For a better understanding of DEVDase activity in plants it would be interesting to know the extent of recombinant VPE inhibition by Ac-DEVD-fmk. This difference of enzyme affinity for a substrate and an inhibitor derived from it illustrates the difficulty of interpreting substrate and inhibitor data in plant extracts.
VPE is a legumain, and legumains are members of the CD clan of cysteine proteases together with caspases, gingipains, and clostripains (Chen et al., 1998). Other legumains such as pig legumain are also able to cleave the caspase-1 substrate Ac-YVAD-AMC, with maximum activity at pH 5 (Rotari et al., 2001). It is therefore expected that plant VPEs cleave YVAD, although the affinity of plant VPE for YVAD appears higher than found using animal legumains. The Km of Ac-YVAD-AMC for recombinant -VPE is 40 µM and is comparable with the Km of Ac-ESEN-AMC, 30 µM. The Km of Ac-YVAD-AMC for purified human caspase-1 has been reported to be 14 µM (Thornberry et al., 2000). It could therefore be proposed that from a common ancestor with animal legumain, plant VPE has evolved to acquire or keep a high affinity against YVAD. This higher affinity would then allow VPE to cleave substrates that are cleaved by caspase-1 in animal cells. However, validation of this hypothesis would first require the identification of in vivo VPE substrates that contain a YVAD cleavage site. Until then, it cannot be excluded that VPE activity against YVAD has no physiological relevance, unlike the long-established VPE activity. Finally, VPE is suggested to ‘moonlight’ as a transcription factor by interacting with the promoter region of 1-aminocyclopropane-1-carboxylic acid synthase, an ethylene biosynthetic enzyme activated by the fungal elicitor ethylene-inducing xylanase (Matarasso et al., 2005). For this, VPE has to enter the nucleus. It is not known at present whether this gene activation function plays a role when PCD is ethylene mediated.
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Saspase, a serine protease with caspase-like activity |
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Caspase inhibitors prevent Rubisco proteolysis during victorin-induced PCD, and the use of the pan-caspase substrate z-VAD-AFC allowed the detection of a caspase-like activity in extracts from victorin-treated Avena sativa leaves. The authors purified the activity, identified at the sequence level a serine protease, and proposed to name it saspase because of its aspartate specificity. Saspase is therefore a serine protease of the subtilisin family that can cleave caspase substrates, is inhibited by caspase inhibitors, and is involved indirectly in victorin-induced cleavage of Rubisco during PCD in oats (Avena sativa) (Coffeen and Wolpert, 2004). Purified saspase showed maximal activity at pH 6.5, and could cleave most caspase substrates tested, with maximum activity against the caspase-6 substrates VKMD, VEHD, and VNLD. Saspase did not cleave VEID (another caspase-6 substrate), WEHD, or DEVD. There was a reduced activity against YVAD (20% of VAD). Saspase appears to function in the extracellular space and this, added to the fact that purified saspase does not cleave Rubisco, suggests that saspase is upstream of a cascade that ultimately leads to the cleavage of Rubisco (Coffeen and Wolpert, 2004). Whether inhibiting specifically saspase would reduce or block PCD is not known.
Saspase is a subtilisin, and subtilisins exist as large multigene families in plants (Meichtry et al., 1999). There are subtilisin genes in the genome of rice and of Arabidopsis that are possible orthologues of the oat saspase identified; however, their substrate specificity has not been analysed. The oat saspase is not the only example of a serine protease with caspase-like cleavage specificity. In animal cells, granzyme B (Thornberry et al., 1997) and the proteasome can also cleave caspase substrates (Kisselev et al., 2003).
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Subcellular localization of caspase-like activities |
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The collapse of the vacuole is thought to be a specific feature of plant PCD (Jones, 2001; van Doorn and Woltering, 2004), and proteases responsible for caspase-like activities could be expected to be localized in that organelle. VPE enzymes are localized in lytic vacuoles of Arabidopsis leaves (Kinoshita et al., 1999) and are thought to be required for the process of vacuole rupture (Hatsugai et al., 2004), hence the link between VPE and completion of PCD. The rationale is that a rupture of the tonoplast would release the hydrolases stored inside it, including proteases, and destroy the cell from within. In support of this mechanism in PCD, several cysteine proteases involved in plant PCD have been shown to be present in vacuoles (Kinoshita et al., 1995), and papain-like cysteine proteases have been localized to the vacuole (Granell et al., 1998).
It is known, however, that other caspase-like activities do not reside in the vacuole but rather in the cytosol, the nucleus, or the cell wall. By micro-injection of a fluorogenic caspase-3 substrate (Ac-DEVD-AMC) in Chara cells, a caspase-3-like activity was found to be present in the cytosol and only weakly in the vacuole (Korthout et al., 2000). In another study using staurosporine-induced PCD in a tobacco cell suspension, the proteins labelled by fluoroisothiocyanate conjugated to a VAD-fmk inhibitor were localized in the cytosol only during the early stages of PCD. At a later stage, the labelled proteins were localized primarily to the nucleus (Elbaz et al., 2002). Similarly, the TATDase is likely to be nuclear (Chichkova et al., 2004). These observations have been confirmed in more detail using Papaver pollen where self-incompatibility activates PCD to stop pollination. A DEVDase is activated early on and a fluorogenic substrate showed this activity to be both cytosolic and nuclear (Bosch and Franklin-Tong, 2007).
A novel and unexpected localization for plant caspase-like proteases is the cell wall. Release of saspase into the extracellular space occurs rapidly before the onset of other markers of PCD. It has therefore been suggested that the export of saspase into the cell wall is not a consequence of PCD but may be part of the induction of PCD (Coffeen and Wolpert, 2004). The importance of the cell wall is possibly further confirmed by the presence of metacaspase-9 (Vercammen et al., 2006). So far, there is no report of caspase-like activity in the mitochondria or chloroplast. How those proteases in various subcellular locations come into play remains to be elucidated.
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Conclusion |
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The inhibition of plant PCD using caspase inhibitors has brought significant progress in our understanding of the process. Protease activities cleaving synthetic caspase substrates and inhibited by caspase inhibitors are not only present in plants but are also central to many PCD processes in various experimental systems. The synthetic substrates used, however, are not caspase specific, but rather represent the optimal cleavage site of specific caspases (Stennicke and Salvesen, 2000). These synthetic caspase substrates can be cleaved by all caspases with various efficiencies and by non-caspase protease in animal cells; for example, legumain cleaves a caspase-1 synthetic substrate. It is therefore not surprising that caspase inhibitors derived from these synthetic substrates are effective against some plant proteases. Inhibition of plant PCD by caspase inhibitors does not automatically imply that there are caspase functional homologues in plants. What is certain is that there are proteases required for the completion of PCD that cleave caspase substrates and are inhibited by caspase inhibitors.
Some progress has been made towards the identification of the proteases involved, and it is now known that the VPE gene family is responsible for the caspase-1 like activity (YVADase) detected in plants. Recombinant -VPE and VPE activity in plants is inhibited by caspase-1 inhibitor; VPE is required for vacuole rupture and VPE inhibition explains the mode of action of caspase-1 inhibitors in plants. Whether it is the ESENase activity of VPE, the YVADase activity, or both activities that are crucial to the progression of PCD remains to be shown. Saspase appears mainly responsible for the plant activities against the caspase-8 substrate IETD and one of the caspase-6 substrates VKMD. The fact that saspase cleaves one caspase-6 substrate (VKMD) but not another (VEID) illustrates that there are probably no plant proteases that have taken over or retained the precise function of a given animal caspase. Possibly a web of activities from various proteases can cleave the portfolio of caspase-optimal substrates.
Several possible scenarios can be used to integrate the role of plant caspase activities in plant PCD. One is that behind the divergence of plant and animal PCD, similarities reveal a common ancestral mechanism of cell self-destruction that comprises cytochrome c release and DNA fragmentation. Metacaspases have been prime candidates as components of an ancestral caspase-like mechanism until it was clearly established that these proteases did not have caspase-like activity. Therefore, metacaspases do not appear functionally equivalent to caspases, and whether a common origin with caspase explains a metacaspase control of PCD is open to debate. Experimental evidence is conflicting but it is still suggestive of a possible role for metacaspases in a subset of PCD pathways. However, it is tenable to put forward the hypothesis that metacaspases may not play a direct role in plant PCD (Vercammen et al., 2007). A second scenario could be that there is a limited set of key proteins to disable in order to obtain an efficient disassembly of cells during PCD. In which case, plant and animal evolution may have homed in on the same targets recruiting unrelated proteases. This would imply the conservation of ubiquitous substrate cleavage sites that would be revealed by caspase inhibitors. Finally the two proteolytic processes may be totally unrelated, the only point of convergence being the importance of proteases. Caspase inhibitors have been helpful protease inhibitors along the way and revealed some of the key proteases. In summary, more proteases with caspase-like activities need to be identified in order to build a robust scenario that integrates the various proteases recruited in the plant PCD pathways. The identification of physiologically relevant, in vivo, protein substrates is even more crucially needed to understand both the plant process and its relationship to PCD in other kingdoms.
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