Sorcietal.CellDeathandDisease(2018)9:796DOI10.1038/s41419-018-0843-zCellDeath&DiseaseARTICLEOpenAccessMETTL3regulatesWTAPproteinhomeostasisMelissaSorci1,ZairaIanniello1,SoniaCruciani1,SimoneLarivera1,LaviniaCeciGinistrelli1,ErnestinaCapuano2,MarcellaMarchioni3,FrancescoFazi2,4andAlessandroFatica1AbstractTheWilmstumor1(WT1)-associatedprotein(WTAP)isupregulatedinmanytumors,including,acutemyeloidleukemia(AML),whereitplaysanoncogenicrolebyinteractingwithdifferentproteinsinvolvedinRNAprocessingandcellproliferation.Inaddition,WTAPisalsoaregulatorofthenuclearcomplexrequiredforthedepositionofN6-methyladenosine(m6A)intomRNAs,containingtheMETTL3methyltransferase.However,itisnotclearifWTAPmayhavem6A-independentregulatoryfunctionsthatmightcontributetoitsoncogenicrole.Here,weshowthatbothknockdownandoverexpressionofMETTL3proteinresultsinWTAPproteinupregulation,indicatingthatMETTL3levelsarecriticalforWTAPproteinhomeostasis.However,weshowthatWTAPupregulationisnotsufficienttopromotecellproliferationintheabsenceofafunctionalMETTL3.Therein,thesedataindicatethatthereportedoncogenicfunctionofWTAPisstrictlyconnectedtoafunctionalm6Amethylationcomplex.IntroductionN6-methyladenosine(m6A)isthemostabundantinternalchemicalmodificationineukaryoticmRNAanditcancontrolanyaspectofmRNApost-transcriptionalregulation1.Inmammals,thewriterofm6Aisanuclearmulticomponentcomplexcomposedoftwomethyltransferase-likeproteins,METTL3andMETTL14,andtheregulatoryproteinsWilmstumor1-associatedprotein(WTAP),virlikem6Amethyltransferaseasso-ciated(VIRMA,alsoknownasKIAA1429),RNA-bindingmotifprotein15(RBM15)andzincfingerCCCH-typecontaining13(ZC3H13)1,2.METTL3isthesolecatalyticcomponentofthecomplexwhileMETTL14functionsinstructuralstabilizationandRNAsubstraterecognition3–5.Morerecently,thehumanU6snRNAm6Amethyl-transferaseMETTL16hasbeenshowntotargetintronicregionsofpre-mRNAsandlncRNAs6,7.Removalofm6AfromtranscriptsoccurspredominantlyinthenucleusandrequirestheactivityofthealkBhomologue5protein(ALKBH5)andfatmassandobesity-...
