Gasdermins:EffectorsofpyroptosisStephenB.KovacsandEdwardA.MiaoDepartmentofMicrobiologyandImmunology,LinebergerComprehensiveCancerCenter,andCenterforGastrointestinalBiologyandDisease,UniversityofNorthCarolinaatChapelHill,ChapelHill,NC27599,USAAbstractPyroptosisisaformoflyticprogrammedcelldeathinitiatedbyinflammasomes,whichdetectcytosoliccontaminationorperturbation.Thisdrivesactivationofcaspase-1orcaspase-11/4/5,whichcleavegasderminD,separatingitsN-terminalpore-formingdomain(PFD)fromtheC-terminalrepressordomain(RD).ThePFDoligomerizestoformlargeporesinthemembranethatdriveswellingandmembranerupture.GasderminDisoneofsix(inhumans)gasderminfamilymembers;severalothergasderminshavealsobeenshowntoformporesthatcausepyroptosisaftercleavagetoactivatetheirPFDs.Oneofthese,gasderminE,isactivatedbycaspase-3cleavage.Wereviewourcurrentunderstandingofpyroptosisaswellascurrentknowledgeofthegasderminfamily.Keywordsgasdermin;pyroptosis;inflammasome;programmedcelldeath;apoptosisPyroptosisdefendsagainstintracellularinfectionImmunecellssuchasphagocytesthatincludemacrophagesandneutrophilsactivelysurveytheextracellularspaceandtargetbacteria,fungi,andparasites.Manypathogensinvadehostcellsand,consequently,avoiddetectionbyphagocytesanddownstreamcellintrinsicdefenses.Thecontinuedexistenceoftheinfectedcellthreatensthehost,andthesolutionistokilltheinfectedcell.Killinginfectedcellscanbeaccomplishedthrougheithercell-intrinsicorcell-extrinsicmechanisms.Ifthecellitselfcanidentifyitscompromisedstate,itwillactivatecell-intrinsicdeathmechanismsthatincludecell-intrinsicapoptosis,necroptosis,andpyroptosis(Glossary).Unfortunately,manyintracellularpathogensevadeorinhibitcell-intrinsicprogrammedcelldeath(Glossary).Ourlastlinesofdefensearecytotoxiccellsintheinnateandadaptiveimmunesystems,includingnaturalkillercellsandcytotoxicT*Correspondence:emiao@med.unc.edu(E.A.Miao).Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyve...
