RESEARCHARTICLEInhibitionofretroviralGagassemblybynon-silencingmiRNAspromotesautophagicviraldegradationNaQu1,ZhaoMa1,MengraoZhang1,MuazN.Rushdi1,2,ChristopherJ.Krueger1,2,AntonyK.Chen1&1DepartmentofBiomedicalEngineering,CollegeofEngineering,PekingUniversity,Beijing100871,China2WallaceHCoulterDepartmentofBiomedicalEngineering,GeorgiaInstituteofTechnology,Atlanta,GA30332,USA&Correspondence:chenak@pku.edu.cn(A.K.Chen)ReceivedJune30,2017AcceptedAugust7,2017ABSTRACTWerecentlyreportedanunconventionalmechanismbywhichmiRNAsinhibitHIV-1viralproduction.ThisoccurswhenmiRNAsbindnonspecificallytotheviralstructuralproteinGag,interferingwithviralRNA-medi-atedGagassemblyattheplasmamembrane.Conse-quently,misassembledviralcomplexesareredirectedintotheendocyticpathwaywheretheyaredeliveredtolysosomesfordegradation.Inthisstudy,wedemon-stratethatautophagyisacriticalmediatoroftheviraldegradationpathwayandthatthispathwayisnotHIV-1specific.MisassembledviralcomplexeswerefoundtocolocalizeextensivelywithLC3andp62inlateendo-somes/lysosomes,demonstratingaconvergenceofautophagywithfunctionaldegradativecompartments.Knockingdownautophagosomeformationmachineriesreducedthisconvergence,whiletreatmentwithautop-hagy-inducerrapamycinenhancedtheconvergence.Furthermore,similarautophagy-dependentnonspecificmiRNAinhibitionofmurineleukemiavirus(MLV)assemblywasshown.Overall,theseresultsrevealautophagyasacrucialregulatoroftheretroviraldegradationpathwayinhostcellsinitiatedbynon-specificmiRNA-Gaginteractions.ThesefindingscouldhavesignificantimplicationsforunderstandinghowcellsmayregulateretroviralcomplexassemblybymiRNAexpressionandautophagy,andraisethepossi-bilitythatsimilarregulationscanoccurinotherbiolog-icalcontexts.KEYWORDSmicroRNA,Gagprotein,autophagyINTRODUCTIONMicroRNAs(miRNAs)aresmallnoncodingRNAs,19–24nucleotidesinlength,withgene-silencingfunctionscriticaltotheregulationofnumerousphysiologicalandpathologicalprocesses(Filipowiczetal.,2008;Sharp,2009).Toachievegenesilencing,miRNAsassociatewiththeRNA-i...
