Nik‐related kinase is targeted for proteasomal degradation by the chaperone‐dependent ubiquitin ligase CHIP
Nik‐related kinase is targeted for proteasomal degradation by the chaperone‐dependent ubiquitin ligase CHIP
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DOI：
10.1002/1873-3468.13769
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发表时间：
2020-03
期刊：
影响因子：
3.5
通讯作者：
Satomi Naito;T. Fukushima;Akinori Endo;K. Denda;M. Komada
中科院分区：
文献类型：
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作者：
Satomi Naito;T. Fukushima;Akinori Endo;K. Denda;M. Komada
Nik相关激酶（Nrk）是生发中心激酶IV家族的成员，可抑制Akt信号传导。在体内，Nrk可以防止胎盘增生和乳腺癌的形成。在这里，我们发现Nrk受热休克蛋白（Hsp）70相互作用蛋白（CHIP）的伴侣依赖性泛素连接酶羧基末端的调控。免疫沉淀和液相色谱-串联质谱分析显示，Nrk优先与CHIP和Hsp70/90家族蛋白相互作用。Nrk蛋白水平因CHIP过表达而降低，而因siRNA介导的CHIP敲低而升高。我们的研究结果表明，Nrk以伴侣依赖的方式被CHIP泛素化，导致其蛋白酶体降解。CHIP靶向的是部分失去调节Akt信号能力的Nrk分子。我们认为CHIP在调控Nrk蛋白水平中起重要作用。
Nik‐related kinase (Nrk) is a member of the germinal center kinase IV family and suppresses Akt signaling. In vivo, Nrk prevents placental hyperplasia and breast cancer formation. Here, we show that Nrk is regulated by the chaperone‐dependent ubiquitin ligase carboxyl terminus of heat‐shock protein (Hsp)70‐interacting protein (CHIP). Immunoprecipitation and liquid chromatography–tandem mass spectrometry analysis reveal that Nrk preferentially interacts with CHIP and Hsp70/90 family proteins. Nrk protein levels are decreased by CHIP overexpression and increased by siRNA‐mediated CHIP knockdown. Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone‐dependent manner, resulting in its proteasomal degradation. CHIP targets a fraction of Nrk molecules that have lost the ability to regulate Akt signaling. We conclude that CHIP plays an important role in regulating Nrk protein levels.