Dual Regulation of the Transcriptional Activity of Nrf1 by β-TrCP- and Hrd1-Dependent Degradation Mechanisms
Dual Regulation of the Transcriptional Activity of Nrf1 by β-TrCP- and Hrd1-Dependent Degradation Mechanisms
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DOI：
10.1128/mcb.05663-11
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发表时间：
2011-11-01
影响因子：
5.3
通讯作者：
Kobayashi, Akira
中科院分区：
文献类型：
--
作者：
Tsuchiya, Yoshiki;Morita, Tomoko;Kobayashi, Akira
越来越多的证据表明Nrf1是一种维持细胞稳态的诱导转录因子。在生理条件下，Nrf1靶向内质网（ER），这意味着它在响应激活信号的情况下易位到细胞核。然而，调控Nrf1功能的分子机制仍然知之甚少。在这里，我们报道了两种不同的降解机制调节Nrf1活性及其靶基因的表达。在细胞核中，β - trcp是SCF （Skp1-Cul1-F-box蛋白）泛素连接酶的接头，通过催化Nrf1的多泛素化来促进Nrf1的降解。该活性需要Nrf1上的DSGLS基序，类似于规范的β - trcp识别基序。短干扰RNA （siRNA）介导的β - trcp沉默显著增加了Nrf1靶基因（如蛋白酶体亚基PSMC4）的表达，表明β - trcp抑制Nrf1的激活。同时，在正常条件下，Nrf1在细胞质中被er相关降解（ERAD）泛素连接酶Hrd1和含缬草苷蛋白（VCP）降解和抑制。我们在NHB1和NHB2结构域之间的Nrf1上发现了一个细胞质降解基序，显示出物种守恒。因此，这些结果清楚地表明β - trcp -和hrd1依赖性降解机制都调节Nrf1的转录活性以维持细胞稳态。
A growing body of evidence suggests that Nrf1 is an inducible transcription factor that maintains cellular homeostasis. Under physiological conditions, Nrf1 is targeted to the endoplasmic reticulum (ER), implying that it translocates into the nucleus in response to an activating signal. However, the molecular mechanisms by which the function of Nrf1 is modulated remain poorly understood. Here, we report that two distinct degradation mechanisms regulate Nrf1 activity and the expression of its target genes. In the nucleus, beta-TrCP, an adaptor for the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase, promotes the degradation of Nrf1 by catalyzing its polyubiquitination. This activity requires a DSGLS motif on Nrf1, which is similar to the canonical beta-TrCP recognition motif. The short interfering RNA (siRNA)-mediated silencing of beta-TrCP markedly augments the expression of Nrf1 target genes, such as the proteasome subunit PSMC4, indicating that beta-TrCP represses Nrf1 activation. Meanwhile, in the cytoplasm, Nrf1 is degraded and suppressed by the ER-associated degradation (ERAD) ubiquitin ligase Hrd1 and valosin-containing protein (VCP) under normal conditions. We identified a cytoplasmic degradation motif on Nrf1 between the NHB1 and NHB2 domains that exhibited species conservation. Thus, these results clearly suggest that both beta-TrCP- and Hrd1-dependent degradation mechanisms regulate the transcriptional activity of Nrf1 to maintain cellular homeostasis.