6July2017|VOl547|NATuRE|99lETTERdoi:10.1038/nature22393Chemotherapydrugsinducepyroptosisthroughcaspase-3cleavageofagasderminyupengWang1,2*,WenqingGao1,2*,XuyanShi1,2,JingjinDing2,3,Wangliu2,HuabinHe2,KunWang2&FengShao2,4Pyroptosisisaformofcelldeaththatiscriticalforimmunity.Itcanbeinducedbythecanonicalcaspase-1inflammasomesorbyactivationofcaspase-4,-5and-11bycytosoliclipopolysaccharide1–3.ThecaspasescleavegasderminD(GSDMD)initsmiddlelinkertoreleaseautoinhibitiononitsgasdermin-Ndomain,whichexecutespyroptosisviaitspore-formingactivity4–9.GSDMDbelongstoagasderminfamilythatsharesthepore-formingdomain4,6,10.Thefunctionsandmechanismsofactivationofothergasderminsareunknown.HereweshowthatGSDME,whichwasoriginallyidentifiedasDFNA5(deafness,autosomaldominant5)11,canswitchcaspase-3-mediatedapoptosisinducedbyTNForchemotherapydrugstopyroptosis.GSDMEwasspecificallycleavedbycaspase-3initslinker,generatingaGSDME-Nfragmentthatperforatesmembranesandtherebyinducespyroptosis.Afterchemotherapy,cleavageofGSDMEbycaspase-3inducedpyroptosisincertainGSDME-expressingcancercells.GSDMEwassilencedinmostcancercellsbutexpressedinmanynormaltissues.HumanprimarycellsexhibitedGSDME-dependentpyroptosisuponactivationofcaspase-3bychemotherapydrugs.Gsdme−/−(alsoknownasDfna5−/−)micewereprotectedfromchemotherapy-inducedtissuedamageandweightloss.Thesefindingssuggestthatcaspase-3activationcantriggernecrosisbycleavingGSDMEandoffernewinsightsintocancerchemotherapy.TherecentidentificationofGSDMDasthepyroptoticsubstrateofcaspase-1,-4,-5and-11(refs4,5)andoftheconservedgasderminfamily4,6hasredefinedpyroptosisasgasdermin-mediatedprogrammednecrosis10.Thegasdermin-NdomainsinGSDMD6–9andtheothergasderminfamilymembersGSDMA3andGSDMA6bindmembranelipidsandperforatethemembrane.Thispore-formingactivitydisruptsosmoticpotential,causingcellswellingwithlargebubblesblowingfromtheplasmamembrane.AllgasderminsexceptforDFNB59sharethepyroptoticgasdermin-Ndomain.Gasderminsaregeneticallyassociatedwithvariousdiseases.Pyroptosis-ac...
