Regulation of amyloid precursor protein processing by the Beclin 1 complex.
Regulation of amyloid precursor protein processing by the Beclin 1 complex.
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DOI：
10.1371/journal.pone.0011102
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发表时间：
2010-06-15
期刊：
影响因子：
3.7
通讯作者：
Wyss-Coray T
中科院分区：
文献类型：
--
作者：
Jaeger PA;Pickford F;Sun CH;Lucin KM;Masliah E;Wyss-Coray T
自噬是一种细胞内降解途径，作用于蛋白质和细胞器的更新，以响应饥饿和细胞应激。自噬是通过形成一个包含Beclin 1(BECN1)及其结合伙伴磷脂酰肌醇-3-激酶3类(PIK3C3)的复合体开始的。最近，BECN1缺乏被证明可以增强阿尔茨海默病(AD)小鼠模型的病理。然而，BECN1或自噬介导这些效应的机制尚不清楚。在这里，我们报告了淀粉样前体蛋白(APP)及其代谢产物的水平可以通过自噬激活而降低，这表明它们是自噬的底物。此外，我们还发现，在细胞培养中敲除Becn1会增加APP及其代谢物的水平。APP和APP C末端片段的积累(APP-CTF)伴随着自噬小体清除受损。药物抑制自噬-溶酶体的降解会导致APP和APP-代谢物在自噬体内的类似积累。在细胞培养中，Becn1的减少导致其结合伙伴Pik3c3的水平降低，而微管相关蛋白1，轻链3(Lc3)的存在增加。另一方面，Becn1的过度表达会降低细胞内APP的水平。与这些观察结果一致，我们在AD患者的大脑中检测到较少的BECN1和PIK3C3，但检测到较多的LC3蛋白。我们得出结论，BECN1调节APP的处理和周转。BECN1参与自噬的启动和自噬小体的清除。因此，BECN1缺乏扰乱细胞自噬和自噬-溶酶体的降解，并改变APP代谢。综上所述，我们的发现表明，自噬和BECN1-PIK3C3复合体调节APP的加工，并在AD病理中发挥重要作用。
Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex containing Beclin 1 (BECN1) and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3). Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD). However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP) and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF) are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3). Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.
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影响因子：
1.7
作者：
Hirayama, A;Horikoshi, Y;Takashima, S
通讯作者：
Takashima, S
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
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