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 (also known as APBB1) is a major APP-binding protein. Regulated intramembrane proteolysis (RIP) by -secretase releases the APP intracellular domain (AICD), together with the interacting proteins, from the membrane. We studied the impact of the Fe65 family (Fe65, and its homologs Fe65L1 and Fe65L2, also known as APBB2 and APBB3, respectively) on the nuclear signaling function of the AICD. All Fe65 family members increased amyloidogenic processing of APP, generating higher levels of β-cleaved APP stubs and AICD. However, Fe65 was the only family member supporting AICD translocation to nuclear spots and its 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 (also known as KAT5) for nuclear translocation. Furthermore, inhibition of APP cleavage reduces nuclear Tip60 levels, but this does not occur 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.

淀粉样前体蛋白 (APP) 是阿尔茨海默病 (AD) 的核心分子，在细胞粘附和信号传导、迁移、神经突生长和突触发生中具有生理作用。细胞内衔接蛋白介导跨膜蛋白的功能。Fe65（也称为 APBB1）是一种主要的 APP 结合蛋白。β-分泌酶调节的膜内蛋白水解 (RIP) 从膜上释放 APP 胞内结构域 (AICD) 以及相互作用的蛋白质。我们研究了 Fe65 家族（Fe65 及其同源物 Fe65L1 和 Fe65L2，分别称为 APBB2 和 APBB3）对 AICD 核信号传导功能的影响。所有 Fe65 家族成员都增加了 APP 的淀粉样蛋白形成过程，产生更高水平的 β-裂解 APP 短片段和 AICD。然而，Fe65 是唯一支持 AICD 易位至核点及其转录活性的家族成员。使用最近建立的转录测定，我们剖析了 Fe65 的转录活性，并提供了 Fe65 代表转录因子的有力证据。我们证明 Fe65 依赖赖氨酸乙酰转移酶 Tip60（也称为 KAT5）进行核转位。此外，抑制 APP 裂解会降低核 Tip60 水平，但这不会发生在 Fe65 敲除细胞中。因此，APP 裂解速率调节 AICD-Fe65-Tip60 (AFT) 复合物的核转位，以促进 Fe65 的转录。