The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1
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DOI：
10.1038/ncb2021
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发表时间：
2010-03-01
影响因子：
21.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Komatsu, Masaaki;Kurokawa, Hirofumi;Yamamoto, Masayuki
自噬导致的p62选择性翻转受损会导致严重的肝损伤，并伴随着p62阳性包涵体的形成和解毒酶的上调。这些表型与人类肝病的病理情况密切相关，包括酒精性肝炎和肝细胞癌。然而，这些事件的分子机制和病理生理过程仍不清楚。在这里，我们报道了转录因子Nrf2的p62基因的一个新的调控机制，其靶基因包括抗氧化蛋白和解毒酶。P62与Keap1上的Nrf2结合位点相互作用，Keap1是Nrf2的cullin-3型泛素连接酶的一个组成部分。因此，p62的过度生产或自噬缺陷与Nrf2和Keap1之间的相互作用竞争，导致Nrf2的稳定和Nrf2靶基因的转录激活。我们的发现表明，与p62积聚相关的病理过程导致Nrf2的过度激活，并描述了选择性自噬在控制细胞防御酶基因转录方面的意外作用。
Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.