Affiliations: [a] Centre for Cell Biology, Health Sciences Department and Biology Department, University of Aveiro, Aveiro, Portugal | [b] Division of Psychiatry Research, University of Zurich, Zurich, Switzerland | [c] Graduate School of Medical Science, University of Hyogo, Hyogo, Japan
Correspondence:
[*]
Correspondence to: Odete A.B. da Cruz e Silva, Centre for Cell Biology, Health Sciences Department, University of Aveiro, 3810-193 Aveiro, Portugal. Tel.: +351 234 370 213; Fax: +351 234 401 597; E-mail: odetecs@ua.pt.
Note: [1] These authors contributed equally to this work.
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.
