AATF inhibits aberrant production of amyloid β peptide 1-42 by interacting directly with par-4
AATF inhibits aberrant production of amyloid β peptide 1-42 by interacting directly with par-4
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DOI：
10.1074/jbc.m309811200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Xie, J
中科院分区：
文献类型：
--
作者：
Guo, Q;Xie, J
神经毒性淀粉样β肽1-42（Abeta-（1-42））在脑中的聚集被认为是阿尔茨海默病（AD）发病机制中的早期事件。Par-4（前列腺凋亡反应-4）是一种亮氨酸拉链蛋白，其是促凋亡的并且与AD中的神经元变性相关。Par-4的过表达显著增加了凋亡级联反应启动后Abeta-（1-42）的产生，表明调节凋亡途径的因子也可能影响β-淀粉样前体蛋白（APP）的加工。AATF（凋亡拮抗转录因子）是近年来发现的与死亡相关蛋白激酶家族成员DAP样激酶（Dlk）相互作用的转录因子。AATF可拮抗Par-4诱导的细胞凋亡，提示AATF可能直接或间接参与Par-4活性的调节。我们现在报告，AATF与Par-4共定位在细胞质和核隔室，它直接和选择性地与Par-4通过亮氨酸拉链结构域在神经细胞中相互作用。在神经母细胞瘤IMR-32细胞中，Par-4诱导凋亡级联反应启动后Abeta的异常产生和分泌。AATF的共表达完全阻断了Par-4诱导的Abeta-（1-42）的异常产生和分泌，AATF/Par-4复合物的形成是AATF抑制Abeta-（1-42）异常分泌的关键。这些结果表明，AATF是Par-4活性的内源性拮抗剂，并且是凋亡条件下异常Abeta产生和分泌的有效抑制剂。
Aggregation of the neurotoxic amyloid beta peptide 1-42 (Abeta-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased production of Abeta-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of beta-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Abeta in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions.