INTESTINALSTRESSPanethcellssecretelysozymeviasecretoryautophagyduringbacterialinfectionoftheintestineShaiBel,1MihirPendse,1YuhaoWang,1YunLi,1KellyA.Ruhn,1BrianHassell,1TessLeal,1SebastianE.Winter,2RamnikJ.Xavier,3,4,5LoraV.Hooper1,6*IntestinalPanethcellslimitbacterialinvasionbysecretingantimicrobialproteins,includinglysozyme.However,invasivepathogenscandisrupttheGolgiapparatus,interferingwithsecretionandcompromisingintestinalantimicrobialdefense.Hereweshowthatduringbacterialinfection,lysozymeisreroutedviasecretoryautophagy,anautophagy-basedalternativesecretionpathway.SecretoryautophagywastriggeredinPanethcellsbybacteria-inducedendoplasmicreticulum(ER)stress,requiredextrinsicsignalsfrominnatelymphoidcells,andlimitedbacterialdissemination.SecretoryautophagywasdisruptedinPanethcellsofmiceharboringamutationinautophagygeneAtg16L1thatconfersincreasedriskforCrohn’sdiseaseinhumans.OurfindingsidentifyaroleforsecretoryautophagyinintestinaldefenseandsuggestwhyCrohn’sdiseaseisassociatedwithgeneticmutationsthataffectboththeERstressresponseandautophagy.Themammalianintestineishometoadiversepopulationofbacteria,whichincludespatho-gensthatcandisrupthostcellularfunctions.Theintestinalepitheliumdefendsagainstbacterialencroachmentthroughmultiplemechanisms,includingantimicrobialproteinsecretionanddestructionofinvadingbacteriathroughautophagy(1).Panethcellsarespecial-izedintestinalepithelialcellsthatsecreteabun-dantantimicrobialproteins,includinglysozyme;thus,disruptingPanethcellsecretioncanleadtoinflammatorydisease(2–4).Pathogenicmicrobescantriggerendoplasmicreticulum(ER)stressthatinterfereswithproteinsecretion(5,6)andcompromisesantimicrobialproteindelivery,rais-ingthequestionofhowPanethcellspreservetheirantimicrobialfunctionduringpathogen-inducedstress.Invasivebacteria,includingSalmonellaentericaserovarTyphimurium(S.Typhimurium),triggerautophagyinintestinalenterocytes.Thisisindi-catedbyabundantepithelialcellautophagosomes,markedbyLC3(microtubule-associatedprotein1lightchain3),tha...
