The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression
The Casein Kinase 2-Nrf1 Axis Controls the Clearance of Ubiquitinated Proteins by Regulating Proteasome Gene Expression
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DOI：
10.1128/mcb.01271-12
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发表时间：
2013-07
影响因子：
5.3
通讯作者：
Yoshiki Tsuchiya;H. Taniguchi;Yoshiyuki Ito;Tomoko Morita;M. Karim;Norihito Ohtake;Kousuke Fukagai;Takao Ito;S. Okamuro;S. Iemura;T. Natsume;E. Nishida;A. Kobayashi
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文献类型：
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作者：
Yoshiki Tsuchiya;H. Taniguchi;Yoshiyuki Ito;Tomoko Morita;M. Karim;Norihito Ohtake;Kousuke Fukagai;Takao Ito;S. Okamuro;S. Iemura;T. Natsume;E. Nishida;A. Kobayashi
泛素-蛋白酶体系统（UPS）的损伤与人类疾病的发病机制有关，包括神经退行性疾病。因此，刺激蛋白酶体活性是改善这些年龄相关疾病的一种有希望的策略。在这里，我们发现蛋白激酶酪蛋白激酶2 （CK2）调节Nrf1的转录活性，以控制蛋白酶体基因的表达，从而清除泛素化蛋白。我们确定CK2是nrf1结合蛋白，并发现CK2的敲低增强了nrf1依赖性蛋白酶体亚基基因的表达。蛋白酶体活性的实时监测显示，CK2敲低可减轻蛋白酶体抑制时泛素化蛋白的积累。此外，我们确定Nrf1的Ser 497是CK2磷酸化位点，并证明其丙氨酸取代（S497A）增强了Nrf1的转录活性，减轻了蛋白酶体抑制时蛋白酶体功能障碍和p62阳性近核包涵体的形成。这些结果表明，ck2介导的Nrf1磷酸化抑制蛋白酶体基因的表达和活性，因此表明CK2-Nrf1轴是UPS损伤相关疾病的潜在治疗靶点。
ABSTRACT Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.