title: RanBP9 modulates AICD localization and transcriptional activity via direct interaction with Tip60.
abstract: Proteolytic processing of the amyloid-β protein precursor (AβPP) occurs via alternative pathways, culminating with the production of the AβPP intracellular domain (AICD). AICD can translocate to the nucleus and regulate transcription, but its activity is modulated by interactions with other proteins. In the nucleus, AICD, FE65, and Tip60 associate into AFT complexes, which are targeted to nuclear spots which correspond to transcription factories. Here we report that RanBP9 interacts with the cytoplasmic domain of AβPP, through the NPXY internalization motif. Moreover, RanBP9 interaction with Tip60 is also described. The RanBP9-Tip60 interaction dramatically relocated RanBP9 from a widespread cellular distribution to nuclear speckles. AβPP processing is a central aspect in determining the protein's function and that of its resulting proteolytic fragments, among them AICD. The latter results from the amyloidogenic pathway and is the peptidic species predominantly involved in nuclear signaling. Of note RanBP9 transfection was previously demonstrated to increase amyloid-β generation. Here we show that RanBP9 relocates AICD to the Tip60-enriched nuclear speckles, and prevented the formation of nuclear spots formation, having therefore a negative effect on AICD mediated nuclear signaling and consequently AFT complex formation. Furthermore, by transfecting cells with increasing amounts of RanBP9, the expression of AICD-regulated genes, including AβPP itself, was reduced. Given the data presented, one can deduce that RanBP9 has an inhibitory regulatory effect on AICD-mediated transcription and the effect is mediated by relocating AICD away from transcription factories.
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Domingues
authors.affiliation: Division of Psychiatry Research, University of Zurich, Zurich, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Konietzko
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Ana Gabriela
authors.initials: AG
authors.lastname: Henriques
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebelo
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Fardilha
authors.affiliation: Graduate School of Medical Science, University of Hyogo, Hyogo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nishitani
authors.affiliation: Division of Psychiatry Research, University of Zurich, Zurich, Switzerland.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Edgar F
authors.initials: EF
authors.lastname: da Cruz E Silva
authors.affiliation: Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal.
authors.forename: Odete A B
authors.initials: OA
authors.lastname: da Cruz E Silva
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D000074443:Lysine Acetyltransferase 5; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D014158:Transcription, Genetic / Q000502:physiology; D020798:Two-Hybrid System Techniques
chemical_list: C091042:APBB1 protein, human; C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C116005:Ran binding protein 9; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5
keywords: AFT spots; Alzheimer's disease; AβPP; Fe65; RanBPM; amyloid-β precursor protein; nuclear signaling; nuclear speckles