title: miRISC and the CCR4-NOT complex silence mRNA targets independently of 43S ribosomal scanning.
abstract: miRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4-NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4-NOT complex in Drosophila melanogaster Here, we show that miRNAs, AGOs, GW182, the CCR4-NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning-independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Duygu
authors.initials: D
authors.lastname: Kuzuoğlu-Öztürk
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Bhandari
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Huntzinger
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Fauser
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Helms
authors.affiliation: Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany elisa.izaurralde@tuebingen.mpg.de.
authors.forename: Elisa
authors.initials: E
authors.lastname: Izaurralde
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D012270:Ribosomes; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D060565:Argonaute Proteins; D001324:Autoantigens; C528690:CNOT1 protein, human; D029721:Drosophila Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C465663:TNRC6A protein, human; D014157:Transcription Factors; C532748:Me31B protein, Drosophila; C094683:DDX6 protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX6; GW182; argonaute; deadenylation; eIF4A