ACCELERATEDARTICLEPREVIEWAcceleratedArticlePreviewLETTERdoi:10.1038/nature22393Chemotherapydrugsinducepyroptosisthroughcaspase-3cleavageofaGasderminYupengWang,WenqingGao,XuyanShi,JingjinDing,WangLiu,HuabinHe,KunWang&FengShaoThisisaPDFfileofapeer-reviewedpaperthathasbeenacceptedforpublication.Althoughunedited,thecontenthasbeensubjectedtopreliminaryformatting.Natureisprovidingthisearlyversionofthetypesetpaperasaservicetoourcustomers.Thetextandfigureswillundergocopyeditingandaproofreviewbeforethepaperispublishedinitsfinalform.Pleasenotethatduringtheproductionprocesserrorsmaybediscoveredwhichcouldaffectthecontent,andalllegaldisclaimersapply.Citethisarticleas:Wang,Y.etal.Chemotherapydrugsinducepyroptosisthroughcaspase-3cleavageofaGasdermin.Naturehttp://dx.doi.org/10.1038/nature22393(2017).Received7March;accepted25April2017.AcceleratedArticlePreviewPublishedonline1May2017.©2017MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.ACCELERATEDARTICLEPREVIEW00MONTH2017|VOL000|NATURE|1LETTERdoi:10.1038/nature22393Chemotherapydrugsinducepyroptosisthroughcaspase-3cleavageofaGasderminYupengWang1,2*,WenqingGao1,2*,XuyanShi1,2,JingjinDing2,3,WangLiu2,HuabinHe2,KunWang2&FengShao2,4Pyroptosis,activatedbythecanonicalcaspase-1inflammasomesorcaspase-4/5/11bycytosolicLPS,iscriticalforimmunity1–3.ThecaspasescleaveGasderminD(GSDMD)inthemiddlelinkertoreleaseautoinhibitiononitsGasdermin-Ndomainthatexecutespyroptosisviathepore-formingactivity4–9.GSDMDbelongstoaGasderminfamilysharingthepore-formingdomain4,6,10.ThefunctionandmechanismofactivationforotherGasderminsareunknown.HereweshowthatGSDME,originallyidentifiedasDFNA5(Deafness,AutosomalDominant5)11,couldswitchTNFαorchemotherapydrugs-inducedandcaspase-3-mediatedapoptosistopyroptosis.GSDMEwasspecificallycleavedbycaspase-3inthelinker,generatingaGSDME-Nfragmentthatperforatedmembranesforpyroptosisinduction.Followingchemotherapydrugstreatment,caspase-3cleavageofGSDMEdeterminedpyroptosisincertainGSDME-expressingcancercells.GSDME...
