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Fe65 is the sole family member mediating transcription regulated by the amyloid precursor protein.

The amyloid precursor protein (APP), a central molecule in Alzheimer's disease (AD), has physiological roles in cell adhesion and signaling, migration, neurite outgrowth and synaptogenesis. Intracellular adapter proteins mediate the function of transmembrane proteins. Fe65 is a major APP-binding protein. Regulated intramembrane proteolysis (RIP) by γ-secretase releases the APP intracellular domain (AICD) together with the interacting proteins from the membrane. We studied the impact of the Fe65 family on the nuclear signaling function of AICD. All Fe65 family members increased amyloidogenic processing of APP, generating higher levels of β-cleaved APP stubs and AICD. Notwithstanding, Fe65 was the only family member supporting AICD translocation to nuclear spots and transcriptional activity. Using a recently established transcription assay, we dissected the transcriptional activity of Fe65 and provide strong evidence that Fe65 represents a transcription factor. We show that Fe65 relies on the lysine acetyltransferase Tip60 for nuclear translocation. Furthermore, inhibition of APP cleavage reduces nuclear Tip60 levels, but not in Fe65 knockout cells. The rate of APP cleavage therefore regulates the nuclear translocation of AICD/Fe65/Tip60 (AFT) complexes, to promote transcription by Fe65.