Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles
Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles
复制标题
DOI：
10.1046/j.1365-2443.2003.00640.x
复制
发表时间：
2003-04-01
期刊：
影响因子：
2.1
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
背景：转录因子Nrf 2调节一组解毒和抗氧化酶基因的表达。一些证据表明，亲电体和活性氧从其细胞质阻遏物Keap 1中释放Nrf 2，并引起Nrf 2在细胞核中的积累。为了阐明诱导剂激活Nrf 2的分子机制，我们检测了Nrf 2的胞质-核穿梭和周转。结果：Nrf 2通过蛋白酶体途径被迅速降解，而亲电试剂则导致Nrf 2核转位并伴随稳定化。Nrf 2的诱导积累的关键是亲电体削弱Nrf 2-Keap 1相互作用。利用小鼠的LacZ报告基因敲入nrf 2基因座，我们发现，诱导积累的Nrf 2蛋白的亲电体在巨噬细胞和肠上皮细胞可以重演的Nrf 2 N-末端区域结合核定位信号。我们还发现了组成型Nrf 2核积累在Keap 1缺陷小鼠macrophages.Conclusions：我们的研究结果突出了这样一个事实，即Nrf 2蛋白营业额由Keap 1介导的亚细胞区室化调节。
Background: Transcription factor Nrf2 regulates the expression of a set of detoxifying and anti-oxidant enzyme genes. Several lines of evidence suggest that electrophiles and reactive oxygen species liberate Nrf2 from its cytoplasmic repressor Keap1 and provoke the accumulation of Nrf2 in the nucleus. To elucidate the molecular mechanisms as to how Nrf2 is activated by inducers, we examined the cytoplasmic-nuclear shuttling and turnover of Nrf2.Results: We found that Nrf2 is rapidly degraded through the proteasome pathway, while electrophiles cause Nrf2 nuclear translocation with concomitant stabilization. Crucial to the inducible accumulation of Nrf2 is the enfeebling of the Nrf2-Keap1 interaction by electrophiles. Exploiting mice which have the LacZ reporter gene knocked into the nrf2 locus, we revealed that the inducible accumulation of Nrf2 protein by electrophiles in macrophages and intestinal epithelia could be recapitulated by the Nrf2 N-terminal region in combination with a nuclear localization signal. We also found constitutive Nrf2 nuclear accumulation in Keap1-deficient mouse macrophages.Conclusions: Our results highlight the fact that Nrf2 protein turnover is regulated by Keap1 mediated subcellular compartmentalization.