β-分泌酶1（BACE1）的类泛素化修饰在阿尔茨海默病病理学中失调磷酸化和泛素化过程。
BACE1 SUMOylation deregulates phosphorylation and ubiquitination in Alzheimer's disease pathology.
作者信息
Zhao Yanna, Zhou Hongyan, Zhao Yan, Liang Zhen, Gong Xiaokang, Yu Jing, Huang Tiantian, Yang Chaoqin, Wu Mengjuan, Xiao Yifan, Yang Youhua, Liu Wei, Wang Xiaochuan, Shu Xiji, Bao Jian
机构信息
Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China.
出版信息
J Neurochem. 2023 Jul;166(2):318-327. doi: 10.1111/jnc.15870. Epub 2023 Jun 7.
BACE1 is essential for the generation of amyloid-β (Aβ) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aβ accumulation.
β-分泌酶1（BACE1）对于淀粉样β蛋白（Aβ）的生成至关重要，而Aβ可能引发阿尔茨海默病（AD）中的毒性作用。BACE1的活性主要受翻译后修饰调控，但这些修饰之间的关系尚未完全明确。在此，我们研究了BACE1的小泛素样修饰（SUMOylation）对其磷酸化和泛素化的影响。我们证明，BACE1的SUMOylation在体外抑制其在S498位点的磷酸化及其泛素化。相反，BACE1在S498位点的磷酸化抑制其SUMOylation，这导致在体外促进BACE1的降解。此外，BACE1 SUMOylation的增加与AD病理进展相关，而在AD小鼠模型中其磷酸化和泛素化则减少。我们的研究结果表明，BACE1的SUMOylation相互影响其磷酸化，并与其泛素化相互竞争，这可能为BACE1活性和Aβ积累的调控提供新的见解。
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