Fig. 2.12 Mechanismsofapoptosis.Thetwopathwaysofapoptosisdifferintheirinductionandregulation,andbothculminateintheactivationofcaspases.Inthemitochondrialpathway,BH3-onlyproteins,whicharerelatedtomembersoftheBcl-2family,sensealackofsurvivalsignalsorDNAorproteindamage.TheseBH3-onlyproteinsactivateeffectormoleculesthatincreasemitochondrialpermeability.InconcertwithadeficiencyofBcl-2andotherproteinsthatmaintainmitochondrialpermeability,themitochondriabecomeleakyandvarioussubstances,suchascytochromec,enterthecytosolandactivatecaspases.Activatedcaspasesinducethechangesthatculminateincelldeathandfragmentation.Inthedeathreceptorpathway,signalsfromplasmamembranereceptorsleadtotheassemblyofadaptorproteinsintoa“death-inducingsignalingcomplex,”whichactivatescaspases,andtheendresultisthesame.
become permeable, cytochrome c leaks out into the cytoplasm, triggering caspase activation and apoptotic death. A family of more than 20 proteins, the prototype of which is Bcl-2, controls the permeability of mitochondria. In healthy cells, Bcl-2 and the related protein Bcl-xL, which are produced in response to growth factors and other stimuli, maintain the integrity of mitochondrial membranes, in large part by holding two proapoptotic members of the family, Bax and Bak, in check. When cells are deprived of growth factors and survival signals, or are exposed to agents that damage DNA, or accumulate unacceptable amounts of misfolded proteins, a number of sensors are activated. These sensors are called BH3 proteins because they contan the third domain seen in Bcl-family proteins. They in turn shift this delicate, life-sustaining balance in favor of pro-apoptotic Bak and Bax. As a result, Bak and Bax dimerize, insert into the mitochondrial membrane, and form channels through which cytochrome c and other mitochondrial proteins escape into the cytosol. After cytochrome c enters the cytosol, it, together with certain cofactors, activates caspase-9. The net result is the activation of a caspase cascade, ultimately leading to nuclear fragmentation and formation of apoptotic bodies.
• The death receptor (extrinsic) pathway of apoptosis. Many cells express surface molecules, called death receptors, that trigger apoptosis. Most of these are members of the tumor necrosis factor (TNF) receptor family, which contain in their cytoplasmic regions a conserved “death domain,” so named because it mediates interaction with other proteins involved in cell death. The prototypic death receptors are the type I TNF receptor and Fas (CD95). Fas ligand (FasL) is a membrane protein expressed mainly on activated T lymphocytes. When these T cells recognize Fas-expressing targets, Fas molecules are crosslinked by FasL and bind adaptor proteins via the death domain. These then recruit and activate caspase-8, which, in turn, activates downstream caspases. The death receptor pathway is involved in the elimination of self-reactive lymphocytes and in the killing of target cells by some cytotoxic T lymphocytes (CTLs) that express FasL.
In either pathway, after caspase-9 or caspase-8 is activated, it cleaves and thereby activates additional caspases that cleave numerous targets and ultimately activate enzymes that degrade the cells’ proteins and nucleus. The end result is the characteristic cellular fragmentation of apoptosis.