ReviewRecentInsightsinto[360_TD$DIF]theMolecularMechanismsUnderlyingPyroptosisandGasderminFamilyFunctionsRobinA.Aglietti1andErinC.Dueber1,*Pyroptosisisaninflammatoryformofcelldeaththatnotonlyprotectsmulti-cellularorganismsfrominvadingpathogenicbacteriaandmicrobialinfections,butcanalsoleadtosepsisandlethalsepticshockifoveractivated.Here,wepresentanoverviewofrecentdevelopmentswithinthepyroptosisfield,begin-ningwiththediscoveryofGasderminD(GSDMD)asasubstrateofcaspase-1andcaspase-11upondetectionofcytosoliclipopolysaccharide(LPS).Cleav-agereleasestheN-terminaldomainofGSDMD,causingittoformcytotoxicporesintheplasmamembraneofcells.Wefurtherdiscusstheimplicationsfortherestofthegasdermin(GSDM)family,whichareemergingasmediatorsofprogrammedcelldeathinavarietyofprocessesthatregulatecellulardifferen-tiationandproliferation.DiscoveryoftheNoncanonicalInflammasomePathwayIn2011,onehalfoftheNobelPrizeinphysiologyormedicinewasawardedjointlytoBruceA.BeutlerandJulesA.Hoffmann‘fortheirdiscoveriesconcerningtheactivationofinnateimmunity’i[361_TD$DIF].TheirworksuggestedthatToll-likereceptor4(TLR-4)mediatesLPS-inducedlethalitybyservingastheLPSsensorresponsibleforinitiatinganinducibleprogramofinflammatorygeneexpression.ThisdiscoverywasakeymilestoneinunderstandinginnateimmunesignalingandsparkednumerousattemptstodevelopTLR-4antagonistsasthera-peuticstargetingsepticshock(Box1).Unfortunately,sucheffortswerenotsuccessful,oftenfailinginclinicaltrialsduetoalackofefficacy[1].Anexplanationforthisdiscrepancycamein2013whentwoconcurrentstudies[2,3]reportedanoncanonicalinflammatorypathwaythatcompletelybypassedtheneedforthecell-surfaceLPSsensor,TLR-4,andinsteadreliedondetectionofcytoplasmicLPSthroughanunknownmechanisminvolvingactivationofcaspase-11(Box2)[4].Subsequentexperimentsconfirmedthesefindingsandsuggestedthatcaspase-11itselfisdirectlyactivatedbyLPSbindingtothecaspase-11caspaseactivationandrecruitmentdomain(CARD),potentiallyservingasanintracellularLPSsensor[5].Moreover,caspase-11wasshowntobecruci...
