OpinionPyroptosis:Gasdermin-MediatedProgrammedNecroticCellDeathJianjinShi,1WenqingGao,1andFengShao1,*Pyroptosiswaslongregardedascaspase-1-mediatedmonocytedeathinresponsetocertainbacterialinsults.Caspase-1isactivateduponvariousinfectiousandimmunologicalchallengesthroughdifferentinflammasomes.Thediscoveryofcaspase-11/4/5functioninsensingintracellularlipopolysac-charideexpandsthespectrumofpyroptosismediatorsandalsorevealsthatpyroptosisisnotcelltypespecific.Recentstudiesidentifiedthepyroptosisexecutioner,gasderminD(GSDMD),asubstrateofbothcaspase-1andcas-pase-11/4/5.GSDMDrepresentsalargegasderminfamilybearinganovelmembranepore-formingactivity.Thus,pyroptosisisredefinedasgasder-min-mediatedprogrammednecrosis.Gasderminsareassociatedwithvariousgeneticdiseases,buttheircellularfunctionandmechanismofactivation(exceptforGSDMD)areunknown.Thegasderminfamilysuggestsanewareaofresearchonpyroptosisfunctioninimmunity,disease,andbeyond.ProgrammedCellDeathandPyroptosisApoptosis,theprototypeofprogrammedcelldeath,isessentialformulticellularorganismdevelopment.Apoptosisfeaturesactivationofthecaspasefamilyofcysteineproteases;theinitiatorcaspasereceivesextrinsicorintrinsicapoptoticcuesandthenactivatestheexecutionercaspasestoinitiatethedeathprogram.Inapoptosis,cellsshrinkandarefragmentedintoapoptoticbodiesthatareusuallyengulfedbysurroundingmacrophages,leadingtothenonin-flammatorynatureofthecelldeath.Inhibitingapoptoticcaspase(caspase-8)inthepresenceoftheproapoptoticstimulustriggersnecroptosis,aformofprogrammednecroticcelldeath,throughthereceptor-interactingserine/threonine-proteinkinase1(RIPK1)–RIPK3-mixedline-agekinasedomain-like(MLKL)axis[1].RIPK3-phosphorylatedMLKLmovestothemembranetoexecutemembranedisruption,causingcellswellingandlysis[2–5].Pyroptosis,theotherformofprogrammednecrosis,isemergingasageneralinnateimmuneeffectormechanisminvertebrates[6].Innateimmunityreliesonpatternrecognitionreceptors(PRRs)todetectconservedmicrobialproductsorendogenousdangers.Besidesinducingcytokinetrans...
