Caspase Functions in Cell Death and Disease

Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Caspase Functions in Cell Death and Disease David R. McIlwain1,2, Thorsten Berger1, and Tak W. Mak The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada Correspondence: [email protected] Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled. aspases are a family of genes important for ingly, caspases have been broadly classified by Cmaintaining homeostasis through regulat- their known roles in apoptosis (caspase-3, -6, ing cell death and inflammation. Here we will -7, -8, and -9 in mammals), and in inflamma- attempt to summarize what we currently know tion (caspase-1, -4, -5, -12 in humans and cas- about how caspases normally work, and what pase-1, -11, and -12 in mice) (Fig. 1). The func- happens when members of this diverse gene tions of caspase-2, -10, and -14 are less easily family fail to work correctly. categorized. Caspases involved in apoptosis Caspases are endoproteases that hydrolyze have been subclassified by their mechanism of peptide bonds in a reaction that depends on action and are either initiator caspases (caspase- catalytic cysteine residues in the caspase active 8 and -9) or executioner caspases (caspase-3, -6, site and occurs only after certain aspartic acid and -7). residues in the substrate. Although caspase-me- Caspases are initially produced as inac- diated processing can result in substrate in- tive monomeric procaspases that require di- activation, it may also generate active signaling merization and often cleavage foractivation. As- molecules that participate in ordered processes sembly into dimers is facilitated by various such as apoptosis and inflammation. Accord- adapter proteins that bind to specific regions in 1These authors contributed equally to this work. 2Present address: Department of Gastroenterology, Hepatology and Infectious Diseases, University of Du¨sseldorf, 40225 Du¨sseldorf, Germany. Editors: Eric H. Baehrecke, Douglas R. Green, Sally Kornbluth, and Guy S. Salvesen Additional Perspectives on Cell Survival and Cell Death available at www.cshperspectives.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a008656 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a008656 1 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press D.R. McIlwain et al. Small subunit Large subunit Apoptosis CARD DED Initiator Executioner Inflammation Caspase 3 Caspase 6 Caspase 7 Caspase 14 Caspase 9 Caspase 2 Caspase 1 Caspase 4 Caspase 5 Caspase 12-L Caspase 12-S Caspase 8 Caspase 10 Figure 1. Domain structure of human caspases. the prodomain of the procaspase. The exact Initiator Caspases mechanism of assembly depends on the specif- The initiator caspases-8 and -9 normally exist as ic adapter involved. Different caspases have dif- inactive procaspase monomers that are activat- ferent protein–protein interaction domains ed by dimerization and not by cleavage. This in their prodomains, allowing them to complex process is generalized as an “induced proximity with different adapters. For example, caspase-1, model” (Muzio et al. 1998; Boatright et al. 2003; -2, -4, -5, and -9 contain a caspase recruitment Chang et al. 2003), in which upstream signaling domain (CARD), whereas caspase-8 and -10 events induce caspase dimerization and activa- have a death effector domain (DED) (Taylor tion. Dimerization also facilitates autocatalytic et al. 2008). cleavage of caspase monomers into one large and one small subunit, which results in stabili- zation of the dimer. PHYSIOLOGICAL CASPASE FUNCTIONS Caspases in Apoptosis Executioner Caspases Apoptosis is programmed cell death that in- Inappropriate activation of the executioner cas- volves the controlled dismantling of intracellu- pases-3, -6, and -7 is prevented by their produc- lar components while avoiding inflammation tion as inactive procaspase dimers that must and damage to surrounding cells. Initiator cas- be cleaved by initiator caspases. This cleavage pases activate executioner caspases that subse- between the large and small subunits allows quently coordinate their activities to demolish a conformational change that brings the two key structural proteins and activate other en- active sites of the executioner caspase dimer to- zymes. The morphological hallmarks of apo- gether and creates a functional mature protease ptosis result, including DNA fragmentation (Riedl and Shi 2004). Once activated, a sin- and membrane blebbing. gle executioner caspase can cleave and activate 2 Cite this article as Cold Spring Harb Perspect Biol 2013;5:a008656 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Caspase Functions in Cell Death and Disease other executioner caspases, leading to an accel- (DR3), TNF-related apoptosis-inducing ligand erated feedback loop of caspase activation. receptor-1 (TRAIL-R1; also called DR4), and TRAIL-R2 (also called DR5 in humans). Ro- dents have only one TRAIL-R protein and it Pathways of Apoptosis resembles DR5. Death receptor ligands include Variousapoptotic pathways exist that can be dis- TNF, CD95-ligand (CD95-L; also called Fas-L), tinguished by the adapters and initiatorcaspases TRAIL (also called Apo2-L), and TNF-like li- involved. Most apoptotic programs fall into ei- gand 1A (TL1A). The binding of a DR ligand to ther the extrinsic or intrinsic category (Fig. 2). a DR causes the monomeric procaspase-8 pro- The Extrinsic Pathway of Apoptosis. Extrinsic tein to be recruited via its DED to the death- apoptosis is triggered by extracellular cues de- inducing signaling complex (DISC) formed at livered in the form of ligands binding to death the cytoplasmic tail of the engaged DR that also receptors (DRs). Death receptors are members includes the adapter protein FAS-associat- of the tumor necrosis factor (TNF) superfami- ed death domain (FADD) or TNFR-associat- ly and include TNF receptor-1 (TNFR1), CD95 ed death domain (TRADD). Recruitment of (also called Fas and APO-1), death receptor 3 caspase-8 monomers results in dimerization Various cellular stresses Ligand Extrinsic Intrinsic Death receptor Death domain BID tBID FADD Pro- caspase Pro- 3,6,7 Cytochrome c caspase 8 Active Active caspase 8 caspase 9 Active Apoptosome caspase 3,6,7 Pro- APAF1 caspase 9 Apoptosis Figure 2. Extrinsic and intrinsic pathways of apoptosis. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/ TRADD), to recruitment, dimerization, and activation of caspase-8. Active caspase-8 then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP,and caspase- 9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases. Cite this article as Cold Spring Harb Perspect Biol 2013;5:a008656 3 Downloaded from http://cshperspectives.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press D.R. McIlwain et al. and activation. Cells from gene-targeted mice such activated APAF1 monomers then assem- deficient for caspase-8 (casp82/2 mice) are ble into an oligomeric complex, the center of thus resistant to DR-induced apoptosis (Juo et which contains the CARDs that recruit and ac- al. 1998; Varfolomeev et al. 1998; Kang et al. tivate caspase-9 (Acehan et al. 2002). The com- 2004), as are cells from mutant mice lacking plex containing cytochrome c, APAF1, and cas- either FADD (Yehet al. 1998) or TRADD, which pase-9 has been termed the apoptosome (Cain are specifically defective for TNF-a-mediated et al. 2002). apoptosis (Chen et al. 2008b). Cytochrome c has a long established role in The outcome of DR-mediated activation of electron transport, and it was shown in 2000 caspase-8 depends on the cell type. In so-called that mammalian cells lacking cytochrome c type I cells, caspase-8 initiates apoptosis direct- could not activate caspases in response to mito- ly by cleaving and thereby activating

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