FoxO mediates APP-induced AICD-dependent cell death.
The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that has a significant role in the pathogenesis of Alzheimer's disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid β (Aβ) peptides and APP intracellular domain (AICD). Although Aβ peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor forkhead box O (FoxO) as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxO-induced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death through AICD, which acts as a transcriptional co-activator of FoxO.
1] Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China [2].
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Wang
1] Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China [2].
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Wang
Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
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Chen
Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
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Huang
Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
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Hu
Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
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Zhang
Department of Anatomy and Neurobiology, School of Medicine, Tongji University, Shanghai, China.
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Ho
Department of Interventional Radiology, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai, China.
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Xue
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D005426:Flight, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014921:Wings, Animal / Q000196:embryology / Q000378:metabolism* / Q000473:pathology
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins