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Death receptors are transmembrane proteinscontaining an extracellular ligand-binding domain, a single transmembranedomain, and an intracellular death domaln, which is required for the receptorsto activate the apoptotic program. The receptors are homotrimers and belong tothe tumor necrosisfactor (TNF) receptor family, which includes a receptor forTNF itself (discussedin Chapter 15) and the Fasdeath receptor.The ligands thatactivate the death receptors are also homotrimers; they are structurally relatedto one another and belong to the TNFfamily of signal proteins.A well-understood example of how death receptors trigger the extrinsicpathway of apoptosis is the activation of Fas on the surface of a target cell by Fasligand on the surface of a killer (c],totoxic) lymphocyte (discussedin Chapter25).
\.Mhenactivated by the binding of Fas ligand, the death domains on thecltosolic tails of the Fas death receptors recruit intracellular adaptor proteins,which in turn recruit initiator procaspases (procaspase-8,procaspase-7}, orboth), forming a death-inducing signaling complex (DISC).
Once activated inthe DISC, the initiator caspasesactivate do'vrmstreamexecutioner procaspasestoinduce apoptosis (Figure 18-6). As we discuss later, in some cells the extrinsicpathway must recruit the intrinsic apoptotic pathway to amplify the caspasecascadein order to kill the cell.Many cells produce inhibitory proteins that act either extracellularly orintracellularly to restrain the extrinsic pathway. For example, some produce cellsurface decoy receptors, which have a ligand-binding domain but not a deathdomain; becausethey can bind a death ligand but cannot activate apoptosis,thedecoys competitively inhibit the death receptors. Cells can also produce intracellular blocking proteins such as Fl14 which resembles an initiator procaspasebut lacks the proteolltic domain; it competes with procaspase-8 and procaspase-10for binding sites in the DISC and thereby inhibits the activation of theseinitiator procaspases.Such inhibitory mechanisms help prevent the inappropriate activation of the extrinsic pathway of apoptosis.In some circumstances, death receptors activate other intracellular signaling pathways that do not lead to apoptosis.TNF receptors, for example, can alsoactivate the NFrB pathway (discussedin Chapter 15), which can promote cell-a p o p t o t i ct a r g e t c e l lFigure 18-6 The extrinsicpathway ofapoptosisactivatedthrough Fasdeathreceptors.Fasligandon the surfaceof akillerlymphocyteactivatesFasdeathreceptorson the surfaceofthe targetcell.Boththe ligandand receptorarehomotrimers.The cytosolictail of Fasthen recruitsthe adaptorproteinFADDvia the deathdomainon eachprotein(FADDstandsfor Fas-associateddeathdomain).EachFADDproteinthenrecruitsan initiatorprocaspase(procaspase-8,procaspase-10, or both)via a death effectordomain on bothFADDand the procaspase,formingadeath-inducingsignalingcomplex(DISC).Withinthe DISC,the initiatorprocaspasemoleculesare broughtintocloseproximity,whichactivatesthem;the activatedprocaspasesthen cleaveone anotherto stabilizethe activatedprotease,which is now a caspase.Activatedcaspase-8and caspase-10then cleaveand activateexecutionerprocaspases,producinga caspasecascade,which leadsto apoptosis.APOPTOS|S1121survivaland activategenesinvolvedin inflammatoryresponses.\.A/hichresponsesdominatedependson the type of cell and the othersignalsactingon it.ThelntrinsicPathwayof ApoptosisDependson MitochondriaCells can also activate their apoptosis program from inside the cell, usually inresponse to injury or other stresses,such as DNA damage or lack of oxygen,nutrients, or extracellular survival signals (discussedlater).
In vertebrate cells,such intracellular activation of the apoptotic death program occurs via theintrinsic pathway of apoptosis,which depends on the releaseinto the cytosol ofmitochondrial proteins that normally reside in the intermembrane space ofthese organelles (see Figure I2-2lA). Some of the released proteins activate acaspaseproteolytic cascadein the cltoplasm, leading to apoptosis.A crucial protein released from mitochondria in the intrinsic pathway iscytochrome c, a water-soluble component of the mitochondrial electron-transport chain. \iVhen released into the cytosol (Figure l8-7), it has an entirely different function: it binds to a procaspase-activatingadaptor protein called Apafl(apoptotic proteaseactiuating factor-l), causing the Apafl to oligomerize into awheel-like heptamer called an apoptosome.
The Apafl proteins in the apoptosome then recruit initiator procaspase proteins (procaspase-9),which are activated by proximity in the apoptosome, just as procaspase-8and -10 proteins areactivated in the DISC. The activated caspase-9molecules then activate downstream executioner procaspasesto induce apoptosis (Figure l8-8).As mentioned earlier, in some cells, the extrinsic pathway must recruit theintrinsic pathway to amplify the apoptotic signal to kill the cell. It does so byactivating a member of tll'e BcI2 family of proteins, which we now discuss.Bcl2ProteinsRegulatethe lntrinsicPathwayof ApoptosisThe intrinsic pathway of apoptosis is tightly regulated to ensure that cells killthemselves only when it is appropriate.
A major class of intracellular regulatorsof apoptosis is the Bcl2 family of proteins, which, like the caspasefamily, hasbeen conserved in evolution from worms to humans; a human Bcl2 protein, forexample, can suppress apoptosis when expressedin C. elegans.(A) CONTROLcytochrome-c-GFP(B) UV TREATEDcytochrome-c-GFPm i t o c h o n d r i adl y e1 0p .anti-cytochromec25umFigure 18-7 Releaseof cytochromecfrom mitochondria during apoptosis.of humanmicrographsFluorescencecancercellsin culture.(A)Thecontrolwith a genecellsweretransfectedofencodinga fusionproteinconsistingcytochromec linkedto greenfluorescentprotein (cytochrome-c-GFP);they werealsotreatedwith a positivelychargedredin mitochondria.dye that accumulatesdistributionofthe greenTheoverfappingandred indicatethat the cytochrome-c(B)CellsGFPis locatedin mitochondria.wereexpressingcytochrome-c-GFPirradiatedwith ultravioletlightto induceapoptosis,and after 5 hoursthey werestainedwith antibodies(in red)againstiscytochromec; the cytochrome-c-GFPThesixcellsin thealsoshown(ingreen).in B havebottom halfof the micrographsreleasedtheir cytochromec frommitochondriainto the cytosol,whereasthe cellsin the upperhalfof thehavenot yet done so.(FrommicrographsJ.C.Goldsteinet al.,Ndf.CellBiol.2:156-162, 2000.With permissionfromLtd.)MacmillanPublishers1122Chapter18:Apoptosis(A)ApaflApafl bycytochromeca n d h y d r o l y s i os fb o u n d d A T Pt o d A D Pr e c r u i t m e nat ndactivationofprocaspase-9apoptosometriggeredb y r e l e a s eo f d A D Pi n e x c h a n g ef o rdATP (or ATP)APOPTOSOMEIIIc a s p a s e -c9l e a v e sa n dt h e r e b ya c t i v a t e se x e c u t i o n e pr r o c a s p a s e sIiCASPASECASCADELEADINGTO APOPTOSIS10"rnmitochondrionMammalian Bcl2 proteins regulate the intrinsic pathway of apoptosismainly by controlling the release of cltochrome c and other intermembranemitochondrial proteins into the cytosol.
Some Bcl2 proteins are pro-apoptoticand promote apoptosis by enhancing the release,whereas others are anti-apoptotic and inhibit apoptosis by blocking the release.The pro-apoptotic and antiapoptotic Bcl2 proteins can bind to each other in various combinations to formheterodimers, in which the two proteins inhibit each other's function. The balance between the activities of these two functional classes of Bcl2 proteinslargely determines whether a mammalian cell lives or dies by the intrinsic pathway of apoptosis.As illustrated in Figure l8-9, the anti-apoptotic Bcl2 proteins, includingBcl2 itself (the founding member of the Bcl2 family) and Bcl-Xr, share four distinctive Bcl2 homology (BH) domains (BH1-4). The pro-apoptotic Bcl2 proteinsconsist of two subfamilies-the 8H123 proteins and the BH3-onlyproteins.
Themain BH123 proteins are Baxand Bak,wh'ich are structurally similar to Bcl2 butlack the BH4 domain. The BH3-only proteins share sequence homology withBcl2 in only the BH3 domain (seeFigure l8-9).\fhen an apoptotic stimulus triggers the intrinsic pathway, the pro-apoptotic BHl23 proteins become activated and aggregateto form oligomers in themitochondrial outer membrane, inducing the releaseof cytochrome c and otherintermembrane proteins by an unknor,vn mechanism (Figure fS-f0). In mammalian cells, Bax and Bak are the main BH123 proteins, and at least one of themis required for the intrinsic pathway of apoptosis to operate: mutant mouse cellsthat lack both proteins are resistant to all pro-apoptotic signals that normallyactivate this pathway.
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