title: Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs.
abstract: Small regulatory RNAs including small interfering RNAs (siRNAs) and microRNAs (miRNAs) guide Argonaute (Ago) proteins to specific target RNAs leading to mRNA destabilization or translational repression. Here, we report the identification of Importin 8 (Imp8) as a component of miRNA-guided regulatory pathways. We show that Imp8 interacts with Ago proteins and localizes to cytoplasmic processing bodies (P bodies), structures involved in RNA metabolism. Furthermore, we detect Ago2 in the nucleus of HeLa cells, and knockdown of Imp8 reduces the nuclear Ago2 pool. Using immunoprecipitations of Ago2-associated mRNAs followed by microarray analysis, we further demonstrate that Imp8 is required for the recruitment of Ago protein complexes to a large set of Ago2-associated target mRNAs, allowing for efficient and specific gene silencing. Therefore, we provide evidence that Imp8 is required for cytoplasmic miRNA-guided gene silencing and affects nuclear localization of Ago proteins.
authors.affiliation: Laboratory of RNA Biology and Center for Integrated Protein Science Munich, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Lasse
authors.initials: L
authors.lastname: Weinmann
authors.forename: Julia
authors.initials: J
authors.lastname: Höck
authors.forename: Tomi
authors.initials: T
authors.lastname: Ivacevic
authors.forename: Thomas
authors.initials: T
authors.lastname: Ohrt
authors.forename: Jörg
authors.initials: J
authors.lastname: Mütze
authors.forename: Petra
authors.initials: P
authors.lastname: Schwille
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
mesh_terms: D021581:Active Transport, Cell Nucleus; D060565:Argonaute Proteins; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; C107282:IPO8 protein, human; D035683:MicroRNAs; D012333:RNA, Messenger; D028961:beta Karyopherins