CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase.
CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase.
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DOI：
10.1111/acel.12335
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发表时间：
2015-08
期刊：
影响因子：
7.8
通讯作者：
Pati U
中科院分区：
文献类型：
--
作者：
Singh AK;Pati U
在阿尔茨海默病（AD）患者中，淀粉样蛋白-β Aβ沉积，即β-分泌酶/BACE 1对淀粉样前体蛋白（APP）的蛋白水解裂解，在脑中形成老年斑。BACE 1激活是由于氧化应激和泛素-蛋白酶体系统（UPS）功能障碍引起的，这与p53失活有关。由于BACE 1的部分抑制可减少Aβ的产生和AD相关的病理，因此它可能是AD治疗的理想靶点。我们已经表明，在神经元和HEK-APP细胞中，BACE 1是E3-连接酶CHIP的新底物，CHIP和BACE 1水平之间存在负相关。CHIP通过促进其泛素化和蛋白酶体降解抑制异位BACE 1水平，从而减少APP加工;它稳定神经元中的APP，从而减少Aβ。CHIPUbox结构域与BACE 1物理相互作用;然而，U-box和TPR结构域对于BACE 1的泛素化和降解都是必需的。此外，BACE 1是p53的下游靶标，并且p53的过表达降低BACE 1水平。在HEK-APP细胞中，CHIP通过稳定p53的DNA结合构象及其与5′ UTR元件（+127至+150）的结合来负调控BACE 1启动子。因此，我们发现CHIP在转录和翻译后水平调节p53介导的BACE 1的反式阻遏。我们认为CHIP-BACE 1-p53反馈环可能控制APP稳定，这可以进一步用于AD的新治疗干预。
In patient with Alzheimer’s disease (AD), deposition of amyloid-beta Aβ, a proteolytic cleavage of amyloid precursor protein (APP) by β-secretase/BACE1, forms senile plaque in the brain. BACE1 activation is caused due to oxidative stresses and dysfunction of ubiquitin–proteasome system (UPS), which is linked to p53 inactivation. As partial suppression of BACE1 attenuates Aβ generation and AD-related pathology, it might be an ideal target for AD treatment. We have shown that both in neurons and in HEK-APP cells, BACE1 is a new substrate of E3-ligase CHIP and an inverse relation exists between CHIP and BACE1 level. CHIP inhibits ectopic BACE1 level by promoting its ubiquitination and proteasomal degradation, thus reducing APP processing; it stabilizes APP in neurons, thus reducing Aβ. CHIPUbox domain physically interacts with BACE1; however, both U-box and TPR domain are essential for ubiquitination and degradation of BACE1. Further, BACE1 is a downstream target of p53 and overexpression of p53 decreases BACE1 level. In HEK-APP cells, CHIP is shown to negatively regulate BACE1 promoter through stabilization of p53’s DNA-binding conformation and its binding upon 5′ UTR element (+127 to +150). We have thus discovered that CHIP regulates p53-mediated trans-repression of BACE1 at both transcriptional and post-translational level. We propose that a CHIP–BACE1–p53 feedback loop might control APP stabilization, which could further be utilized for new therapeutic intervention in AD.