pharmacologically(药理学的)

Autophagyandviability:pro-survivalorpro-death?CompoundingtheintriguewasthediscoverythatBeclin1interactswithBcl-2,suggestingsurprisingnovelcrosstalkbetweentwopotentialcelldeathpathways.Twoopposinghypotheseshaveemerged:autophagyassistsinthedeathofcellsorautophagyprotectsthecellfromdeath.Recentevidencesuggeststhatbothhypothesesmaybecorrectdependingonthecelltype,stimulianddevelopmentalstage.autophagypromotescellsurvivalduringnutrientstarvationbydegradingandrecyclingnutrients.Autophagymayalsoindirectlypromotecellsurvivalbyretardingorpreventingapoptosis.autophagyplaysacrucialroleincellsurvivalduringPCDEg:Whenautophagyiscompromisedgeneticallyorpharmacologically（药理学的）,HeLacellsdieviaanapoptoticpathway.ThisdeathisabolishedusingBcl-2orcaspaseinhibitorssuggestingthatautophagyprolongssurvivalbydeterringtheonsetofapoptosis.autophagyitselfisa‘pro-death’processorresultsincelldeathbyregulatingapoptosisDuringDrosophila(果蝇）development,autophagyisessentialtoactivatethePCDrequiredtoeliminateunwantedsalivaryglands.Consistentwiththisconcept,severalDrosophilaATGgenesareupregulatedindyingsalivaryglandsintheabsenceofapoptosis,autophagycanactivelycontributetoexecutionofcelldeath.OverexpressionofBcl-2orBcl-XL（AutophagymediateddeathseemstodependonBcl-XL）inwild-typemouseembryonicfibroblaststreatedwithetoposide(足叶乙甙）,（acommonapoptoticreagent）,resultedinincreasedautophagosomeFormation,becauseanincreaseinautophagosomeformationwascorrelatedwithcelldeath.Thenon-apoptoticdeathwasdependentonfunctionalautophagicmechanisms.becausesilencingofATG5/beclin1abolisheddeathwhentreatedwithetoposide.Whetherautophagyfunctionsincellsurvivalorcelldeathmaydependonthelevelofautophagyinducedduringagivenphysiologicalcondition.Autophagyasanantimicrobialdefencemechanismautophagyplaysanimportantroleintheeliminationofintracellularandextracellularpathogens.Eg:theplantvirusTMVaccumulatedtoahigherlevelinBeclin1-silencedplantsthaninwild-typeplantsTheseresultsindicatethatautophagyfunctionsasanantiviraldefencemechanism.TheincreaseinvirusaccumulationinautophagydeficientcellssuggeststhatATGproteinsmighttargetcellularfactorsorpathwaysrequiredforvirusreplicationandspread.Autophagyinducedbynutrientstarvationorbytreatmentwithrapamycin(雷帕霉素）activelyinhibitsthesurvivalofthefacultativeintracellularpathogenMycobacteriumtuberculosis（肺结核分支杆菌）Similarly,autophagicvesicleseffectivelyengulfanddestroyinvadingextracellularpathogenssuchasgroupAStreptococcus（链球菌）(GAS).（Autophagy-deficientatg5-/-mutantEScellsareincapableofeliminatingGAS,allowingittosurviveandProliferate.）Inanimals,recentfindingsindicatethatautophagyisalsousedtocombatagainstbacterialpathogens.Itseemssomebacteriahaveevolvedeffectivecounter-defencestrategiestosubvertautophagyandpromotesuccessfulinfection.1、SomebacterialandviralpathogenshaveevolvedtoutilizetheautophagymachineryforreplicationorsurvivalinsidethehostcellAutophagosomal-likevesiclesprovideareplicativenichefora（varietyofpathogensincludingLegionellapneumophila,andBru-ellaabortus.）2、Whilehidinginsideautophagosomes,thesepathogenseplicateandeitherrestrictsautophagosomematurationordelayfusionwiththelysosome.3、TheinvasivepathogenPorphyromonasgingivalisevenstimulatesautophagosomeformationandusesthemtoenterthehostcells.4、Similarly,poliovirusandmousehepatitisvirus(MHV)inducetheformationofautophagosome-likedouble-membranevesicles(DMV)andusethemasareplicativeniche.eg:Inatg5-/-EScellsinfectedwithMHV,formationofDMVisinhibitedandreplicationofthevirusisdrasticallyreducedindicatingthatautophagyisrequiredforefficientreplicationofMHV