Regulation of USP25 by SP1 Associates with Amyloidogenesis.
Regulation of USP25 by SP1 Associates with Amyloidogenesis.
复制标题
DOI：
10.3233/jad-221184
复制
发表时间：
2023-03
期刊：
影响因子：
--
通讯作者：
Ran Li;Beibei Song;Lu Xu;Jianguo Zheng;Wenhao Pan;Fang Cai;Juelu Wang;Yili Wu;Weihong Song
中科院分区：
文献类型：
--
作者：
Ran Li;Beibei Song;Lu Xu;Jianguo Zheng;Wenhao Pan;Fang Cai;Juelu Wang;Yili Wu;Weihong Song
背景21三体是人类21号染色体（HSA 21）的额外拷贝，导致大多数唐氏综合征（DS）病例。患有DS的个体在中年后不可避免地发展阿尔茨海默病（AD）神经病理学表型，包括淀粉样蛋白斑块和tau神经元缠结。泛素特异性肽酶25（Ubiquitin Specific Peptidase 25，USP 25）是由HSA 21上的USP 25基因编码的一种去泛素化酶，在DS和AD的发病机制中起重要作用。然而，USP 25的监管仍不清楚。目的探讨特异性蛋白1（SP1）对神经细胞内USP 25的调控及其在淀粉样蛋白形成中的作用。方法采用SMART-RACE和Dual-luciferase分析鉴定转录起始位点和启动子活性。EMSA检测功能性SP1反应元件。通过RT-PCR和免疫印迹检测USP 25表达。应用学生t检验或单因素方差分析或统计分析。结果确定了人USP 25基因的转录起始位点。揭示了人USP 25基因中3个功能性SP1应答元件。SP1促进USP 25转录和随后的USP 25蛋白表达，而SP1抑制显著降低非神经元和神经元细胞中的USP 25表达。此外，SP1抑制显著减少淀粉样蛋白生成。结论转录因子SP1调控USP 25基因的表达，与淀粉样变性有关。提示SP1信号通路可能在USP 25的调控中发挥重要作用，并参与USP 25介导的DS和AD发病机制。
BACKGROUND Trisomy 21, an extra copy of human chromosome 21 (HSA21), causes most Down's syndrome (DS) cases. Individuals with DS inevitably develop Alzheimer's disease (AD) neuropathological phenotypes after middle age including amyloid plaques and tau neurofibrillary tangles. Ubiquitin Specific Peptidase 25 (USP25), encoding by USP25 gene located on HSA21, is a deubiquitinating enzyme, which plays an important role in both DS and AD pathogenesis. However, the regulation of USP25 remains unclear. OBJECTIVE We aimed to determine the regulation of USP25 by specificity protein 1 (SP1) in neuronal cells and its potential role in amyloidogenesis. METHODS The transcription start site and promoter activity was identified by SMART-RACE and Dual-luciferase assay. Functional SP1-responsive elements were examined by EMSA. USP25 expression was examined by RT-PCR and immunoblotting. Student's t-test or one-way ANOVA were applied or statistical analysis. RESULTS The transcription start site of human USP25 gene was identified. Three functional SP1 responsive elements in human USP25 gene were revealed. SP1 promotes USP25 transcription and subsequent USP25 protein expression, while SP1 inhibition significantly reduces USP25 expression in both non-neuronal and neuronal cells. Moreover, SP1 inhibition dramatically reduces amyloidogenesis. CONCLUSION We demonstrates that transcription factor SP1 regulates USP25 gene expression, which associates with amyloidogenesis. It suggests that SP1 signaling may play an important role in USP25 regulation and contribute to USP25-mediated DS and AD pathogenesis.