Abstract
Apoptosis is coordinated by members of the caspase family of aspartic acid-specific proteases. Other members of this protease family also play essential roles in inflammation where they participate in the maturation of pro-inflammatory cytokines. To date, almost 400 substrates for the apoptosis-associated caspases have been reported and there are likely to be hundreds more yet to be discovered. Thus, the fraction of the proteome that is degraded (the degradome) by caspases during the demolition phase of apoptosis appears to be quite substantial. Despite this, we still know surprisingly little concerning how caspases provoke some of the signature events in apoptosis, such as membrane phosphatidylserine externalization, cellular retraction, chromatin condensation and apoptotic body production. The inflammatory caspases appear to be much more specific proteases than those involved in apoptosis and only two confirmed substrates for these proteases have been described to date. Here, we have compiled a comprehensive list of caspase substrates and describe a searchable web resource (The Casbah; www.casbah.ie) which contains information pertaining to all currently known caspase substrates. We also discuss some of the unresolved issues relating to caspase-dependent events in apoptosis and inflammation.
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Abbreviations
- RIP-1:
-
receptor-interacting serine/threonine-protein kinase 1
- ICAD:
-
inhibitor of caspase-activated DNase
- CAD:
-
caspase-activated DNase
- iPLA2:
-
calcium independent phospholipase A2
References
Fuentes-Prior P, Salvesen GS . The protein structures that shape caspase activity, specificity, activation and inhibition. Biochem J 2004; 384: 201–232.
Adrain C, Brumatti G, Martin SJ . Apoptosomes: protease activation platforms to die from Trends. Biochem Sci 2006; 31: 243–247.
Martin SJ . Destabilizing influences in apoptosis: sowing the seeds of IAP destruction. Cell 2002; 109: 793–796.
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 1999; 144: 281–292.
Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM . Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 1999; 274: 5053–5060.
Rehm M, Dussmann H, Janicke RU, Tavare JM, Kogel D, Prehn JH . Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process Role of caspase-3. J Biol Chem 2002; 277: 24506–24514.
Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005; 23: 479–490.
Zimmermann KC, Ricci JE, Droin NM, Green DR . The role of ARK in stress-induced apoptosis in Drosophila cells. J Cell Biol 2002; 156: 1077–1087.
Leist M, Jaattela M . Triggering of apoptosis by cathepsins. Cell Death Differ 2001; 8: 324–326.
Egger L, Schneider J, Rheme C, Tapernoux M, Hacki J, Borner C . Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions. Cell Death Differ 2003; 10: 1188–1203.
Chipuk JE, Green DR . Do inducers of apoptosis trigger caspase-independent cell death? Nat Rev Mol Cell Biol 2005; 6: 268–275.
Kroemer G, Martin SJ . Caspase-independent cell death. Nat Med 2005; 11: 725–730.
Adrain C, Martin SJ . The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 2001; 26: 390–397.
Deshmukh M, Kuida K, Johnson Jr EM . Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J Cell Biol 2000; 150: 131–143.
Potts MB, Vaughn AE, McDonough H, Patterson C, Deshmukh M . Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J Cell Biol 2005; 171: 925–930.
Ellis HM, Horvitz HR . Genetic control of programmed cell death in the nematode C. elegans. Cell 1986; 44: 817–829.
Shaham S, Reddien PW, Davies B, Horvitz HR . Mutational analysis of the Caenorhabditis elegans cell-death gene ced-3. Genetics 1999; 153: 1655–1671.
Daish T, Harvey KF, Pfleger CM, Hariharan IK, Kumar S . The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. J Cell Biol 2006; 172: 809–815.
Daish TJ, Mills K, Kumar S . Drosophila caspase DRONC is required for specific developmental cell death pathways and stress-induced apoptosis. Dev Cell 2004; 7: 909–915.
Chew SK, Akdemir F, Chen P, Lu WJ, Mills K, Daish T et al. The apical caspase dronc governs programmed and unprogrammed cell death in Drosophila. Dev Cell 2004; 7: 897–907.
Xu D, Li Y, Arcaro M, Lackey M, Bergmann A . The CARD-carrying caspase Dronc is essential for most, but not all, developmental cell death in Drosophila. Development 2005; 132: 2125–2134.
Zheng TS, Hunot S, Kuida K, Flavell RA . Caspase knockouts: matters of life and death. Cell Death Differ 1999; 6: 1043–1053.
Los M, Wesselborg S, Schulze-Osthoff K . The role of caspases in development, immunity, and apoptotic signal transduction: lessons from knockout mice. Immunity 1999; 10: 629–639.
Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P . Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 1998; 94: 727–737.
Janicke RU, Sprengart ML, Wati MR, Porter AG . Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998; 273: 9357–9360.
Li H, Zhu H, Xu CJ, Yuan J . Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998; 94: 491–501.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 1998; 94: 481–490.
Lin Y, Devin A, Rodriguez Y, Liu ZG . Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 1999; 13: 2514–2526.
Martinon F, Holler N, Richard C, Tschopp J . Activation of a pro-apoptotic amplification loop through inhibition of NF-kappaB-dependent survival signals by caspase-mediated inactivation of RIP. FEBS Lett 2000; 468: 134–136.
Janicke RU, Ng P, Sprengart ML, Porter AG . Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. J Biol Chem 1998; 273: 15540–15545.
Slee EA, Adrain C, Martin SJ . Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 2001; 276: 7320–7326.
Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 1997; 272: 17907–17911.
Stennicke HR, Salvesen GS . Biochemical characteristics of caspases-3, -6, -7, and -8. J Biol Chem 1997; 272: 25719–25723.
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 1996; 384: 368–372.
Houde C, Banks KG, Coulombe N, Rasper D, Grimm E, Roy S et al. Caspase-7 expanded function and intrinsic expression level underlies strain-specific brain phenotype of caspase-3-null mice. J Neurosci 2004; 24: 9977–9984.
Zandy AJ, Lakhani S, Zheng T, Flavell RA, Bassnett S . Role of the executioner caspases during lens development. J Biol Chem 2005; 280: 30263–30272.
Lakhani SA, Masud A, Kuida K, Porter Jr GA, Booth CJ, Mehal WZ et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 2006; 311: 847–851.
Lazebnik YA, Takahashi A, Moir RD, Goldman RD, Poirier GG, Kaufmann SH et al. Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution. Proc Natl Acad Sci USA 1995; 92: 9042–9046.
Takahashi A, Alnemri ES, Lazebnik YA, Fernandes-Alnemri T, Litwack G, Moir RD et al. Cleavage of lamin A by Mch2 alpha but not CPP32: multiple interleukin 1 beta-converting enzyme-related proteases with distinct substrate recognition properties are active in apoptosis. Proc Natl Acad Sci USA 1996; 93: 8395–8400.
Cowling V, Downward J . Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ 2002; 9: 1046–1056.
Murphy BM, O'Neill AJ, Adrain C, Watson RW, Martin SJ . The apoptosome pathway to caspase activation in primary human neutrophils exhibits dramatically reduced requirements for cytochrome C. J Exp Med 2003; 197: 625–632.
Kerr JF, Wyllie AH, Currie AR . Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.
Wyllie AH . Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 1980; 284: 555–556.
McCarthy NJ, Whyte MK, Gilbert CS, Evan G . Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol 1997; 136: 215–227.
Susin SA, Daugas E, Ravagnan L, Samejima K, Zamzami N, Loeffler M et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med 2000; 192: 571–580.
Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF . Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 2001; 3: 339–345.
Croft DR, Coleman ML, Li S, Robertson D, Sullivan T, Stewart CL et al. Actin–myosin-based contraction is responsible for apoptotic nuclear disintegration. J Cell Biol 2005; 168: 245–255.
Rao L, Perez D, White E . Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol 1996; 135: 1441–1455.
Sebbagh M, Renvoize C, Hamelin J, Riche N, Bertoglio J, Breard J . Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 2001; 3: 346–352.
Mills JC, Stone NL, Erhardt J, Pittman RN . Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation. J Cell Biol 1998; 140: 627–636.
Cotter TG, Lennon SV, Glynn JM, Green DR . Microfilament-disrupting agents prevent the formation of apoptotic bodies in tumor cells undergoing apoptosis. Cancer Res 1992; 52: 997–1005.
Liu X, Zou H, Slaughter C, Wang X . DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 1997; 89: 175–184.
Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D et al. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 1998; 12: 806–819.
Savill J, Dransfield I, Gregory C, Haslett C . A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2002; 2: 965–975.
Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med 1995; 182: 1545–1556.
Martin SJ, Finucane DM, Amarante-Mendes GP, O'Brien GA, Green DR . Phosphatidylserine externalization during CD95-induced apoptosis of cells and cytoplasts requires ICE/CED-3 protease activity. J Biol Chem 1996; 271: 28753–28756.
Lauber K, Bohn E, Krober SM, Xiao YJ, Blumenthal SG, Lindemann RK et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 2003; 113: 717–730.
Acknowledgements
We are indebted to Science Foundation Ireland for their support of ongoing work in our laboratory. SJM is a Science Foundation Ireland Principal Investigator (PI1/B038).
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Lüthi, A., Martin, S. The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14, 641–650 (2007). https://doi.org/10.1038/sj.cdd.4402103
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DOI: https://doi.org/10.1038/sj.cdd.4402103
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