RolesofCaspasesinNecroticCellDeathJunyingYuan1,2,*,AyazNajafov1,2,andBenedictePy31DepartmentofCellBiology,HarvardMedicalSchool,240LongwoodAve.Boston,MA02115,USA2LudwigCancerCenter,HarvardMedicalSchool,240LongwoodAve.Boston,MA02115,USA3CIRI,InsermU1111,UniversitéClaudeBernardLyon1,CNRSUMR5308,ÉcoleNormaleSupérieuredeLyon,UniversitédeLyon,F-69007,LYON,FranceAbstractCaspaseswereoriginallyidentifiedasimportantmediatorsofinflammatoryresponseandapoptosis.Recentdiscoveries,however,haveunveiledtheirrolesinmediatingandsuppressingtworegulatedformsofnecroticcelldeath,respectivelytermedpyroptosisandnecroptosis.Theserecentadvanceshavesignificantlyexpandedourunderstandingoftherolesofcaspasesinregulatingdevelopment,adulthomeostasisandhostdefenseresponse.Caspase-1wasfirstreportedintwoseminalstudiesastheprocessingenzymeforpro-interleukin-1β[namedinterleukin-1βconvertingenzyme(ICE)atthetime]thatmediatestheproductionofmatureIL-1β,animportantpro-inflammatorycytokineinvolvedinmultitudeofhumandiseases(Cerrettietal.,1992;Thornberryetal.,1992).Theaminoacidsequencehomologyofcaspase-1withCed-3,encodedbyagenecriticallyinvolvedinregulatingdevelopmentalcelldeathinthenematodeC.elegans,providedthefirsthintforapotentialroleofcaspasesinapoptosisinmammaliancells(Yuanetal.,1993).Thispredictionwasdirectlyverifiedbytheexpressionofcaspase-1orCed-3inculturedfibroblastcellsthatleadtocelldeathwithapoptoticmorphologyandwhichwasinhibitedupontheexpressionofBcl-2orCrmA,aviralinhibitorofcaspases(Miuraetal.,1993).Furthermore,theexpressionofCrmAandBcl-2blockedneuronalcelldeathmediatedbytrophicfactordeprivation,aparadigmmimickingdevelopmentalneuronalcelldeath(Gagliardinietal.,1994).Thesefindingsledtotremendousinterestsinthemolecularmechanismsofapoptosisandthediscoveryofacascadeofactivatedcaspasesintheexecutionofthisregulateddeathsentence.Thecleavageofdifferentsubstratesbycaspasesismechanisticallyresponsibleforthemorphologicalandbiochemicalcharacteristicsofapoptoticcelldeath,includingmembraneblebbing,expo...
