The Fe65 protein family, which comprises Fe65, Fe65L1 and Fe65L2, interacts with amyloid precursor protein (APP), a determinant molecule for Alzheimer's disease, through the APP intracellular domain (AICD). Upon cleavage of APP, Fe65–AICD complexes translocate to the nucleus, where they colocalise with the lysine acetyltransferase Tip60. This leads to the formation of AICD–Fe65–Tip60 (AFT) spots, which function as transcription sites. Several studies have focused on this pathway, but the molecular details of AFT spot formation and the contribution of each Fe65 protein in transcriptional activation are still poorly understood. Now, Uwe Konietzko and colleagues (Probst et al., 2020) perform a detailed analysis of Fe65 proteins in APP-dependent transcriptional regulation. By expressing different truncations of Fe65, the authors determine the different domains required for nuclear translocation, AFT spot formation and transcriptional activation. Interestingly, the interaction with Tip60 promotes Fe65 nuclear translocation. All three Fe65 proteins can induce APP processing, but only Fe65 and Fe65L2 translocate into the nucleus. Most importantly, only Fe65 can form AFT spots and initiate transcriptional activity. Chimeras of Fe65L1 and Fe65L2 with the N terminus of Fe65 were not able to rescue AFT formation and transcription activity, pointing to a multi-domain regulation of these processes. This study singles out Fe65 as a transcriptional regulator and highlights the importance of APP processing in the regulation of Fe65 function.

• © 2020. Published by The Company of Biologists Ltd