Caspases.pdf

Caspase-8479479480416435276303293404377434242111111111111216219372369376315330316330175282323119?180198206171193297316270289311330Ile152374384LigandCellulardamageDISCEXTRINSICINTRINSICMitochondrionApoptosomeApoptosisInitiator caspaseEffector caspaseActivationby dimerizationActivation byintradomain cleavagePrimary cleavageSecondary cleavageRecruitment domainsCARDDEDCatalytic domain subunitsLarge(p20)Small(p10)Caspase-9Caspase-2Caspase-3Caspase-1Caspase-14Caspase-4Caspase-5Caspase-7Caspase-6Caspase-10C-FLIPL384376384376216374374330330330330330315315315330330316316180180175281752062062319819819319323171171404316316119297297377289289270270434330242Ile152Catalytic domain subunitsSmall(p10)330Small(p10)Catalytic domain subunitsSmall(p10)3113111Ile152Catalytic domain subunitsLarge(p20)Catalytic domain subunitsCatalytic domain subunitsCatalytic domain subunits369369315315219372372219372372372Recruitment domainsDEDRecruitment domainsCARD1?HCHCRRRYQHCRHCRHCRHCRHCRHCRHCRHCRHCRC3,7ApoptosomeC9SmacXIAPBcl-2BaxBH3C8,10DISCEXTRINSICDeathreceptorApoptosis InitiatorsACTIVATION MECHANISMApoptotic SignalingKeratinocyte differentiationInflammationApoptosis Effectors476 Cell 147,October 14,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.09.030See online version for legend and references.SnapShot:CaspasesGuy S.Salvesen1 and Avi Ashkenazi21Sanford-Burnham Medical Research Institute,La Jolla,CA 92037,USA 2Genentech,Inc.,South San Francisco,CA 94080,USASnapShot:CaspasesGuy S.Salvesen1 and Avi Ashkenazi21Sanford-Burnham Medical Research Institute,La Jolla,CA 92037,USA 2Genentech,Inc.,South San Francisco,CA 94080,USA476.e1 Cell 147,October 14,2011 2011 Elsevier Inc.DOI 10.1016/j.cell.2011.09.030Caspases(cysteine-dependent aspartate-specific proteases)use a Cys side chain to cleave Asp-containing polypeptide substrates(Alnemri et al.,1996;Fuentes-Prior and Salvesen,2004).They perform selective,limited cleavage of key cellular signaling components.Caspases play important roles in metazoan embryogenesis and homeostasis,regulating diverse biological processes such as programmed cell death,inflammation,cell differentiation,proliferation,and motility(Li and Yuan,2008).The first member of the class(caspase-1)was identified as a protease that converts prointerleukin-1(IL-1)into a mature cytokine.It was later shown to activate apoptosis and possess structural and functional similarity to the essential C.elegans programmed cell death gene ced-3.Mouse caspase-8 is syntenic to human caspase-8 and-10;mouse caspase-11 is syntenic to human caspase-4 and-5.Caspase-12 is perplexing because it is expressed as a truncated protein lacking the catalytic domain or an inactive mutant in various mammals,includ-ing most human racial groups.C.elegans and Drosophila possess fewer caspase genes than do zebrafish or mammals;however,more primitive metazoans(e.g.,sea anenomies)and vertebrates have similar caspase diversity,indicating early evolution of this gene family.FunctionMammalian caspases fall into three major categories based on structural and functional considerations.However,some of the proapoptotic caspases also have nonapoptotic roles in processes such as lymphocyte proliferation,cell motility,and tissue invasion(Kuranaga and Miura,2007).Proapoptotic Caspases.Proapoptotic caspases operate in cascade fashion to cleave a number of cellular proteins,ultimately leading to the cells apoptotic demise.They are subclassified into initiators and effectors.The initiators can be further divided based on their participation in the cell-intrinsic(caspase-9)or cell-extrinsic(caspase-8 and-10)apoptotic pathways.The effectors cleave hundreds of cellular proteins.Which of these are essential for apoptosis and which are“innocent bystanders”is still hotly debated.Proinflammatory Caspases.Proinflammatory caspases mediate the maturation of specific cytokines during activation of the innate immune response but also may participate in a form of cell death known as pyroptosis.Keratinocyte Differentiation.Caspase-14 is involved in keratinocyte differentiation without playing a significant role in inflammation or apoptosis.Structure,Activation Mechanisms,and PlatformsWhereas initiator caspases activate effectors by proteolytic processing,nonproteolytic signals stimulate the initiators themselves.Initially it was thought that all caspases are activated by proteolysis(and this still appears in some reviews and text books).However,it has become clear that this mechanism pertains principally to the effectors,caspase-3,-6,and-7.Structural studies suggest that all caspases share the same fundamental catalytic fold.The active form is an obligate dimer,but the latent(zymogen)form of initia-tors is monomeric,whereas that of effectors is dimeric.During activation and/or maturation,the catalytic region is cleaved into a large(20 kDa)and a small(10 kDa)subunit;together,these form a characteristic(p20/p10)2 holoenzyme.The large subunit contains the catalytic Cys and His dyad,and the small subunit supplies several residues that form the substrate-binding groove,including an essential Arginine.The unstructured regions linking the N-terminal recruitment domain(s)and the C-terminal catalytic portion,or the two catalytic subunits,are often the subject of(auto)proteolysis during maturation.Initiator caspases are engaged through a conserved mechanism that requires the formation of an oligomeric platform,which recruits and activates the protease by proximity-induced dimerization.This process is best understood for caspase-9 in the cell-intrinsic apoptotic pathway.Cell stressors such as DNA damage alter the intracellular balance of interactions between pro-and antiapoptotic members of the Bcl-2 protein family,driving release of mitochondrial cytochrome C into the cytosol.This promotes assembly of an oligomeric apoptosome that recruits and activates caspase-9 via the adaptor Apaf-1 and its cofactor dATP(Riedl and Salvesen,2007).Although structural data are sparse,an analogous platform known as the inflammasome appears to mediate the activation of proinflammatory caspases(Martinon et al.,2002).The inflammasome is composed of cytosolic NOD-like receptors,usually bridged to the caspase by the adaptor protein ASC.An important variation on this theme occurs in the cell-extrinsic apoptotic pathway.Here,death ligands belonging to the tumor necrosis factor(TNF)superfamily activate the apoptotic initiators caspsae-8 and-10 via an oligomerization platform called the death-inducing signaling complex(DISC)(Wilson et al.,2009).Death ligands induce clustering of cognate death receptors such as Fas or DR5 at the cell surface.The clustered receptors assemble a DISC by recruiting caspase-8 or-10 via the adaptor FADD.Dimerization of caspase-8 or-10 within the DISC triggers activation,which is reinforced by excision of the intercatalytic domain linker(Fuentes-Prior and Salvesen,2004)and by polyubiquitina-tion on the p10 subunit(Jin et al.,2009).A cytoplasmic complex,nucleated downstream of TNF receptor 1 by the Ser/Thr kinase RIP1 and FADD,also can stimulate caspase-8.Caspase-8 activates the effectors caspase-3 and-7 either directly(type I signaling)or indirectly by processing the Bcl-2 homology domain 3 protein Bid(type II signaling).cFLIPL is a caspase-8-related protein that lacks the essential catalytic residues but preserves the caspase fold.cFLIPL operates at the DISC as a dual modulator.At high concentrations,it inhibits initiator caspase activation;however,at low levels,it augments stimulation by forming heterodimers with caspase-8 or-10.cFLIPL/caspase-8 heterodimers also may support survival through inhibition of necroptotic cell death(Oberst et al.,2011).Yet another oligomerization platform called the PIDDosome promotes activation of caspase-2 in response to DNA damage via the adaptors PIDD and RAIDD;however,alter-native caspase-2 activation mechanisms may exist as well(Manzl et al.,2009).In summary,caspases are distinguished by their unique ability to cleave substrates at Aspartate residues.They play key roles in metazoan embryogenesis and homeostasis,controlling important processes such as apoptosis and inflammation.They share many structural and mechanistic features and operate in cascade mode.Initiator zymogens are monomeric:their dimerization triggers activation,which is further reinforced by proteolytic processing and higher-order oligomerization.Effector zymogens are dimeric:their cleavage by initiators triggers activation,which is further propagated by activated effectors.Many important questions about caspases remain unanswered,including how they participate in unconventional processes such as proliferation and how their activity is switched off.RefeRencesAlnemri,E.S.,Livingston,D.J.,Nicholson,D.W.,Salvesen,G.,Thornberry,N.A.,Wong,W.W.,and Yuan,J.(1996).Human ICE/CED-3 protease nomenclature.Cell 87,171.Fuentes-Prior,P.,and Salvesen,G.S.(2004).The protein structures that shape caspase activity,specificity,activation and inhibition.Biochem.J.384,201232.Jin,Z.,Li,Y.,Pitti,R.,Lawrence,D.,Pham,V.C.,Lill,J.R.,and Ashkenazi,A.(2009).Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling.Cell 137,721735.Kuranaga,E.,and Miura,M.(2007).Nonapoptotic functions of caspases:caspases as regulatory molecules for immunity and cell-fate determination.Trends Cell Biol.17,135144.Li,J.,and Yuan,J.(2008).Caspases in apoptosis and beyond.Oncogene 27,61946206.Manzl,C.,Krumschnabel,G.,Bock,F.,Sohm,B.,Labi,V.,Baumgartner,F.,Logette,E.,Tschopp,J.,Villunger,A.,and Mayor,A.(2009).Caspase-2 activation in the absence of PID-Dosome formation.J.Cell Biol.185,291303.Martinon,F.,Burns,K.,and Tschopp,J.(2002).The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.Mol.Cell 10,417426.Oberst,A.,Dillon,C.P.,Weinlich,R.,McCormick,L.L.,Fitzgerald,P.,Pop,C.,Hakem,R.,Salvesen,G.S.,and Green,D.R.(2011).Catalytic activity of the caspase-8-FLIP(L)complex inhibits RIPK3-dependent necrosis.Nature 471,363367.Riedl,S.J.,and Salvesen,G.S.(2007).The apoptosome:signalling platform of cell death.Nat.Rev.Mol.Cell Biol.8,405413.Wilson,N.S.,Dixit,V.,and Ashkenazi,A.(2009).Death receptor signal transducers:nodes of coordination in immune signaling networks.Nat.Immunol.10,348355.