Upf1 contributes to Arc/Arg3.1gene expression

Abstract

spatiotemporallocalizationinordertocarryouttheircriticalfunctions.ThemRNAtranscriptforthesynapticprotein,Activity-regulatedcytoskeleton-associatedprotein(Arc,alsoknownasArg3.1),containstwoconserved3’untranslatedregion(UTR)introns,andconsequently,wasproposedanaturaltargetfornonsense-mediatedmRNAdecay(NMD). ThismechanismwasthoughttofunctionasacriticalbrakeonArcproteinsynthesis,allowingprecisecontrolofgeneexpression.TheRNAhelicaseUpf1isamajorcomponentoftheNMDmachinery,however,aspecificroleforthisproteinintheregulationofArcgeneexpressionremainsunclear.Here,wedemonstratethatUpf1functionsatthetranscriptionalandtranslationalleveltopromotealowbasallevelofArcgeneexpression.Specifically, Upf1suppressesArctranscriptionbyenhancingdestabilizationofmRNAsencodingvarioustranscriptionfactors.Upf1alsobindstotheArc3’UTR,resultingintranslationalsuppression.Surprisingly,however,theArctranscriptescapesfromUpf1-mediatedNMDbybindingtoAgo2/miRISC,whichblocksNMDandfurthersuppressesArcmRNAtranslation.Finally,weshowthatsustainedArcexpressionresultingfromreducedlevelsofUpf1contributestoCofilinhyperphosphorylationandabnormalneuronaloutgrowth. Collectively,thesedatarevealanewparadigmforArcgeneregulationandsuggestthatmultiplelevelsofUpf1-mediatedinhibitionmayallowneuronstomorerapidlyandeffectivelyrespondtochangesinneuronalactivity.