The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor
The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor
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DOI：
10.1242/jcs.01323
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发表时间：
2004-09-01
影响因子：
4
通讯作者：
Konietzko, U
中科院分区：
文献类型：
--
作者：
von Rotz, RC;Kohli, BM;Konietzko, U
β -淀粉样蛋白前体蛋白（APP）的生理功能可能包括核信号。为了表征APP接头蛋白Fe65、Jip1b、X11alpha （MINT1）和染色质相关蛋白Tip60的作用，我们通过共聚焦显微镜和共免疫沉淀分析了它们的相互作用。与S3-cleaved APP相对应的AICD与Fe65结合，将其运送到细胞核并停靠在Tip60上。这些蛋白形成AICD-Fe65-Tip60 （AFT）复合物，集中在球形核点上。APP接头蛋白Jip1b也能将AICD转运至细胞核并与Tip60对接，但AICD-Jip1b-Tip60 （AJT）复合物具有不同的斑点状形态。相比之下，X11alpha在细胞质中捕获了AICD。诱导的AICD表达鉴定出APP效应基因APP、BACE、Tip60、gsk3 β和KAI1，而notch效应基因Hes1未作为转录靶点。这些数据确定了APP在核信号传导中的作用，并提示设计用于调节APP裂解的治疗策略会影响aicd依赖性信号传导。
The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11alpha (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. gamma-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11alpha trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3beta and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.