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Many Cuts to Ruin: a Comprehensive Update of Caspase Substrates

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Many Cuts to Ruin: a Comprehensive Update of Caspase Substrates Cell Death and Differentiation (2003) 10, 76–100 & 2003 Nature Publishing Group All rights reserved 1350-9047/03 $25.00 www.nature.com/cdd Review Many cuts to ruin: a comprehensive update of caspase substrates U Fischer1,RUJa¨nicke1 and K Schulze-Osthoff*,1 signal transduction and transcription-regulatory proteins, cell cycle controlling components and proteins involved in DNA 1 Institute of Molecular Medicine, University of Du¨sseldorf, Germany replication and repair. Since then, the number of caspase * Corresponding author: K Schulze-Osthoff, Institute of Molecular Medicine, substrates has considerably increased, more recently in University of Du¨sseldorf, Universita¨tsstrasse 1, D-40225 Du¨sseldorf, Germany particular because of a systematic proteome analysis of Tel: +49 211 8112608; Fax +49 211 8115756; E-mail: [email protected] apoptotic cells.2–4 To date, more than 280 caspase targets are identified. Various methods have been employed to search for Received 29.2.02; accepted 30.9.02 Edited by G Mellino caspase substrates, including direct cDNA pool expression strategies or two-hybrid cloning approaches.5,6 By compara- tive two-dimensional (2D) gel electrophoresis of healthy and apoptotic cells, often a few hundred altered protein spots can Abstract be detected. Although not all of them have been confirmed as Apoptotic cell death is executed by the caspase-mediated caspase targets, such proteomic approaches will certainly cleavage of various vital proteins. Elucidating the conse- lead to the identification of numerous additional substrates in quences of this endoproteolytic cleavage is crucial for our the near future (Table 1). understanding of cell death and other biological processes. Already now, a bewildering number of substrates are cleaved Many caspase substrates are just cleaved as bystanders, by caspases. However, it should be kept in mind that some proteins might be cleaved very late and less completely during because they happen to contain a caspase cleavage site in their apoptosis, or not in all cell types. For example, it has been sequence. Several targets, however, have a discrete function in reported that b-actin can be cleaved by caspases in pheochro- propagation of the cell death process. Many structural and mocytoma and ovarian carcinoma cells,7,8 whereas in many regulatory proteins are inactivated by caspases, while other other cell types no cleavage was detected.9 Thus, it is possible substrates can be activated. In most cases, the consequences that certain protein cleavages are cell type-specific, which may of this gain-of-function are poorly understood. Caspase be because of variations in the expression of individual substrates can regulate the key morphological changes in caspases. Also, caspase cleavage sites are not always apoptosis. Several caspase substrates also act as transducers conserved in different species. For instance, cyclin A is cleaved 10 and amplifiers that determine the apoptotic threshold and cell during apoptosis of Xenopus oocytes, but the caspase fate. This review summarizes the known caspase substrates cleavage site is not present in homologues of mammalian comprising a bewildering list of more than 280 different cells. Some proteins, such as DNase-X, contain one or more classical cleavage sites in their sequence. However, the protein proteins. We highlight some recent aspects inferred by the is virtually not cleaved inside apoptotic cells despite massive cleavage of certain proteins in apoptosis. We also discuss caspase activation.11 Moreover, in some cases, a first cut by emerging themes of caspase cleavage in other forms of cell caspases unleashes additional cleavage sites for other types of death and, in particular, in apparently unrelated processes, proteases. Cleavage of acinus, for instance, by caspase-3 is such as cell cycle regulation and cellular differentiation. necessary but not sufficient to activate its DNA-condensing Cell Death and Differentiation (2003) 10, 76–100. doi:10.1038/ activity. For full activation, an additional, still unknown serine sj.cdd.4401160 protease has to intervene. Only the combined action of both proteases generates the mature fragment, which, when added 12 Keywords: apoptosis; caspase; caspase substrate; proteolysis; to purified nuclei, causes chromatin condensation. signal transduction For many of the identified substrates, the functional consequences of their cleavage are unknown and have only Abbreviations: See Table 1 been inferred from their normal functions. In other cases, the role of caspase cleavage has been experimentally assessed by expressing substrate proteins that have mutant caspase cleavage sites or by expressing protein fragments of the Introduction caspase-cleaved products. Given the high conservation of In 1998, we published a list of caspase substrates comprising the apoptotic phenotype, from worms to mammals, it is highly 65 different proteins that were cleaved by proteases of the likely that a conserved group of crucial caspase substrates caspase family.1 Most of the substrates known at that time exist. Proteolysis of the latter substrates presumably could be categorized into a few functional groups, including leads to the stereotypical destructive alterations that we call proteins involved in scaffolding of the cytoplasm and nucleus, apoptosis. Caspase substrates U Fischer et al 77 Table 1 List of known caspase substrates Substrateb Physiological Function Cleavage Effect Consequences of Cleavage Cleavage Sitesa References 1. Apoptosis regulators Apaf-1 Apoptosome component Inactivated? SVTD (271) and a second 43, 44 unknown site Bad Proapoptotic Bcl-2 protein Activated Cleavage product proapoptotic, Human: EQED (14) 45 if overexpressed Mouse: SATD (61) Bax Proapoptotic Bcl-2 protein Unknown FIQD (33) 46, 47 Bcl-2 Apoptosis inhibitor Inactivated Generation of a proapoptotic DAGD (34) 48 fragment Bcl-xL Apoptosis inhibitor Inactivated Generation of a proapoptotic HLAD (61), SSLD (76) 49, 50 fragment Bid Apoptosis activator Activated Generation of a proapoptotic LQTD (59) 14, 16, 51, 52 fragment that is myristoylated; phosphorylation inhibits cleavage c-FLIP Caspase-8 inhibitor LEVD (376) 53 c-IAP1 Caspase inhibitor Inactivated Generation of a proapoptotic ENAD (372) 54 fragment Procaspases Procaspase-1-14 Activated Activation by proteolytic XXXD For a review see processing Earnshaw et al.55 XIAP Caspase inhibitor Inactivated? Generation of two fragments SESD (242) 56, 57 with distinct inhibitory activity for caspase-3, -7 and -9. Cleaved XIAP is less antiapoptotic and ineffective to activate NF-kB 2. Cell adhesion APC Adenomatous polyposis coli protein Cleavage separates b-catenin DNID (777) 58, 59 binding region and N-terminal armadillo repeat CALM Clathrin assembly protein of Inactivated Unknown 60 myeloid leukemia (syn. AP180), promotes assembly of clathrin triskelia into clathrin cages Cas Crk-associated substrate Inactivated Contributes to disassembly of DVPD (416), DSPD (748) 61, 62 (p130cas), associates with FAK, focal adhesion complexes, paxillin, involved in integrin interrupts extracellular survival signaling signals b-Catenin Cell adhesion and WNT/wingless Inactivated Reduced a-catenin binding and SYLD (32), ADID (83), TQFD 61, 63–65 signaling pathway, constituent of cell–cell contact, reduced (115), YPVD (751), DLMD adherens junctions transcriptional activity, (764) relocalization to the cytoplasm g-Catenin Adherens junction protein (syn. Inactivated Relocalization to the Unknown 61, 64, 66 plakoglobin) cytoplasm, involved in cell dismantling Desmoglein-3 Major transmembrane component Inactivated Loss of cell–cell contacts DYAD (781) and additional 67 of desmosomes unknown sites Desmocollin 3 Component of desmosomes Inactivated Loss of cell–cell contacts Unknown 67 Desmoplakin Desomoplakin-1, -2, components Inactivated Loss of cell–cell contacts Unknown 67 of desmosomes E-cadherin Calcium-dependent adhesion Inactivated Rather late cleavage may DTRD (750) 68, 69 protein in adherens juctions contribute to disruption of cell– cell contacts N-cadherin Calcium-dependent cell adhesion Inactivated Unknown 70 protein P-cadherin Cell adhesion protein in adherens Inactivated? Rather late cleavage may be Putative site: ETAD (695) 69 junctions involved in loss of cell–cell contacts FAK Focal adhesion kinase, tyrosine Inactivated Cleavage leads to disassembly DQTD (772) 71–74 kinase involved in formation of of the focal adhesion complex, contact sites to extracellular matrix cell detachment and interruption of survival signals HEF1 Human enhancer of filamentation 1, Inactivated Disruption of antiapoptotic DLVD (363), DDYD (630) 75, 76 member of the docking protein integrin signaling family, involved in integrin signaling Connexin 45.6 Lens gap junction protein Inactivated Cleavage at a noncanonical DEVE (367) 77 site; phosphorylation by casein kinase II prevents degradation Paxillin Component of the focal adhesion Inactivated Cleavage results in focal Early: NPQD (102), SQLD 78, 79 complex adhesion disassembly and (301) detachment Late: DDLD (5), SELD (146), FPAD (165), SLLD (222) Plakophilin-1 Component of desmosomes Inactivated Loss of cell–cell contacts Unknown 67 3. Cytoskeletal and structural proteins a-Actin Cardiac actin, myofilament protein Inactivated Rather inefficient cleavage by Unknown 80 caspase-3, involved in myofibrillar damage Cell Death and Differentiation Caspase substrates U Fischer et al 78 Table 1 (continued ) Substrate Physiological Function Cleavage Effect Consequences of Cleavage Cleavage Sitesa
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