BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer's disease.
BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer's disease.
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BACE1 SUMO 化可提高其稳定性并增强阿尔茨海默病中的蛋白酶活性
DOI：
10.1073/pnas.1800498115
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发表时间：
2018-04-10
影响因子：
11.1
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Bao J;Qin M;Mahaman YAR;Zhang B;Huang F;Zeng K;Xia Y;Ke D;Wang Q;Liu R;Wang JZ;Ye K;Wang X
BACE1是淀粉样蛋白-多肽生成的限速酶，在阿尔茨海默病（AD）发病机制中起着至关重要的作用。然而，这种必要的蛋白酶是如何在翻译后被调节的仍然不完全清楚。在目前的研究中，我们发现泛素修饰位点BACE1上的K501残基也被竞争性地sumoylation。我们发现，SUMOylation BACE1增强其稳定性和酶活性，导致老年斑形成和认知缺陷。发现BACE1的翻译后修饰有助于深入了解AD的分子机制。淀粉样蛋白β (a β)是阿尔茨海默病（AD）的主要病理标志物，主要受淀粉样前体蛋白（APP）的限制性β分泌酶（即BACE1）裂解调控。然而，BACE1的活性是如何被翻译后调控的，目前还不完全清楚。在这里，我们发现BACE1主要在K501残基上被SUMOylated，这增加了它的蛋白酶活性和稳定性，随后增加了Aβ的产生，导致在AD小鼠模型中看到的认知缺陷。与未sumoylated的K501R突变体相比，注射野生型BACE1可显著增加a β的产生并引发认知功能障碍。此外，在APP/PS1 AD小鼠模型中，野生型BACE1而非非summoylated的K501R突变体的过表达促进了老年斑的形成，加重了认知缺陷。总之，我们的数据强烈表明，BACE1上的K501 SUMOylation在介导其稳定性和酶活性方面起着关键作用。
BACE1 is a rate-limiting enzyme for amyloid beta polypeptide production, which plays a crucial role in Alzheimer’s disease (AD) pathogenesis. However, how this essential protease is posttranslationally regulated remains incompletely understood. In the current study, we show that K501 residue on BACE1, a ubiquitin modification site, is also competitively SUMOylated. We discovered that SUMOylation of BACE1 augments its stability and enzymatic activity, resulting in senile plaque formation and cognitive defect. Identification of the posttranslational modification on BACE1 provides insight into the molecular mechanism in AD. Amyloid beta (Aβ) is a major pathological marker in Alzheimer’s disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here, we show that BACE1 is predominantly SUMOylated at K501 residue, which escalates its protease activity and stability and subsequently increases Aβ production, leading to cognitive defect seen in the AD mouse model. Compared with a non-SUMOylated K501R mutant, injection of wild-type BACE1 significantly increases Aβ production and triggers cognitive dysfunction. Furthermore, overexpression of wild-type BACE1, but not non-SUMOylated K501R mutant, facilitates senile plaque formation and aggravates the cognitive deficit seen in the APP/PS1 AD mouse model. Together, our data strongly suggest that K501 SUMOylation on BACE1 plays a critical role in mediating its stability and enzymatic activity.
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DOI：
10.1523/jneurosci.6473-11.2012
发表时间：
2012-08-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lefort R;Pozueta J;Shelanski M
通讯作者：
Shelanski M
DOI：
10.1016/j.jalz.2010.04.006
发表时间：
2010-09
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Iqbal K;Grundke-Iqbal I
通讯作者：
Grundke-Iqbal I
影响因子：
4.8
作者：
Kang, Eugene L.;Biscaro, Barbara;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
4.8
作者：
Kang, Eugene L.;Cameron, Andrew N.;Tesco, Giuseppina
通讯作者：
Tesco, Giuseppina
影响因子：
11.1
作者：
Kizuka Y;Kitazume S;Fujinawa R;Saito T;Iwata N;Saido TC;Nakano M;Yamaguchi Y;Hashimoto Y;Staufenbiel M;Hatsuta H;Murayama S;Manya H;Endo T;Taniguchi N
通讯作者：
Taniguchi N