期刊
JOURNAL OF CELL SCIENCE
卷 133, 期 17, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.242917
关键词
APBB1; APP; Fe65L1; Fe65L2; Nuclear signaling; Transcription assay
类别
资金
- Swiss National Science Foundation SNF (Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung) [31003A_166177]
- Swiss National Science Foundation (SNF) [31003A_166177] Funding Source: Swiss National Science Foundation (SNF)
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 gamma-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 beta-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.
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