©2016NatureAmerica,Inc.Allrightsreserved.natureimmunologyaDVaNCEONLINEPUBLICaTIONArticlesMtb,thecausativeagentofthediseasetuberculosis,remainstheleadingworldwidebacterialcauseofdeath.Mtbsurvivesinmono-nuclearcells,whereitsuccessfullycombatsmacrophagemicrobicidalmechanismsbyevadingdeliverytothelysosome,therebylimitingbacterialdegradation1.Autophagycancontributetothedegradationofintracellularbacteria(xenophagy)throughtheformationofautophagosomesthatsequestercytoplasmicbacillianddeliverthemtolysosomesfordegradation.Autophagyisalsoimportantforinnateandadaptiveimmuneresponses,asitpromotesantigenpresenta-tionandmodulatesinflammatoryresponses.Itsimportanceinhostimmunityisunderscoredbytheobservationthatmanyintracel-lularpathogenshavestrategiestoevadeautophagy2.InthecaseofMtb,whenautophagyisstimulatedbypharmacologicalmeansorinterferon-γ(IFN-γ)treatment,targetingofMtbtoautophagosomesandbacterialkillingisenhanced3–5.However,intheabsenceofsuchstimuli,themajorityofMtbdonotassociatewithLC3,amarkerofautophagy.Moreover,inrestingmacrophagesandinvivoinmice,autophagyonlymakesamodestcontributiontotheclear-anceofMtb3,6–8.TheseobservationsraisethepossibilitythatMtbblocksautophagy.DuringMtbinfection,xenophagyisinitiatedwhenmycobacte-rialDNAisdetectedbythecytosolicDNAsensorcGAS(‘cyclicGMP-AMPsynthase’)6,9–11.Oncethisprocessisinitiated,over30proteins,includingmembersoftheautophagy-relatedATGfamily,orchestratesequentialmembraneremodelingandtraffickingeventstocompletenucleationoftheautophagosomemembrane(Beclin-1,VPS34andATG14L),elongationandmaturationofautophagosomes(ATG5,ATG12,ATG16L1,ATG4B,ATG3,ATG7andLC3),anddockingandfusionoflysosomes(Syntaxin17andUVRAG)12,13.Transcriptionalreinforcementisneededtosustainautophagybyreplenishingcomponentsthataredegradedalongwithcapturedcargo,suchasadaptorsthatbindcargo(forexample,p62)andLC3,whichinitsphosphatidylethanolamine-conjugatedform(LC3-II)isassociatedwiththeautophagosomalmembrane.Thetranscrip-tionfactorsFOXO3(ref.14)andTFEB15,whichareacti...
