The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor.
The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11alpha (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. gamma-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11alpha trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3beta and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.
Division of Psychiatry Research, University of Zurich, August Forel-Str. 1, 8008 Zurich, Switzerland.
Ruth C
RC
von Rotz
Bernhard M
BM
Kohli
Jérôme
J
Bosset
Michelle
M
Meier
Toshiharu
T
Suzuki
Roger M
RM
Nitsch
Uwe
U
Konietzko
D000123:Acetyltransferases / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D031541:Fluorescence Resonance Energy Transfer; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051861:Kangai-1 Protein; D000074443:Lysine Acetyltransferase 5; D008562:Membrane Glycoproteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000502:physiology*
D000123:Acetyltransferases; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins; D051861:Kangai-1 Protein; D000074443:Lysine Acetyltransferase 5; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000072056:Transcription Factor HES-1; C091042:APBB1 protein, human; C497688:CD82 protein, human; C078493:HES1 protein, human; C098489:KAT5 protein, human