Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy
Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy
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DOI：
10.1016/j.molcel.2013.08.003
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发表时间：
2013-09-12
期刊：
影响因子：
16
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
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作者：
Ichimura, Yoshinobu;Waguri, Satoshi;Komatsu, Masaaki
Keap 1-Nrf 2系统和自噬都参与氧化应激反应、代谢途径和先天免疫，这些过程的失调与致病过程有关。然而，这两种途径之间的相互作用在很大程度上仍然是未知的。在这里，我们表明，自噬衔接蛋白p62的磷酸化显着增加p62的Keap 1，负责降解Nrf 2的Cul 3-泛素E3连接酶复合物的衔接子的结合亲和力。因此，p62磷酸化诱导细胞保护性Nrf 2靶标的表达。p62被组装在选择性的自噬货物上，例如泛素化的细胞器，随后以mTORC 1依赖的方式磷酸化，这意味着Keap 1-Nrf 2系统与自噬的偶联。此外，通过磷酸化p62的积累持续激活Nrf 2有助于人肝细胞癌（HCC）的生长。这些结果表明，选择性自噬和Keap 1-Nrf 2通路是相互依赖的，磷酸化p62和Keap 1之间的相互作用的抑制剂具有作为抗人HCC的治疗剂的潜力。
The Keap1-Nrf2 system and autophagy are both involved in the oxidative-stress response, metabolic pathways, and innate immunity, and dysregulation of these processes is associated with pathogenic processes. However, the interplay between these two pathways remains largely unknown. Here, we show that phosphorylation of the autophagy-adaptor protein p62 markedly increases p62's binding affinity for Keap1, an adaptor of the Cul3-ubiquitin E3 ligase complex responsible for degrading Nrf2. Thus, p62 phosphorylation induces expression of cytoprotective Nrf2 targets. p62 is assembled on selective autophagic cargos such as ubiquitinated organelles and subsequently phosphorylated in an mTORC1-dependent manner, implying coupling of the Keap1-Nrf2 system to autophagy. Furthermore, persistent activation of Nrf2 through accumulation of phosphorylated p62 contributes to the growth of human hepatocellular carcinomas (HCCs). These results demonstrate that selective autophagy and the Keap1-Nrf2 pathway are interdependent, and that inhibitors of the interaction between phosphorylated p62 and Keap1 have potential as therapeutic agents against human HCC.