p62 links autophagy and Nrf2 signaling.
p62 links autophagy and Nrf2 signaling.
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DOI：
10.1016/j.freeradbiomed.2015.06.014
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发表时间：
2015-11
影响因子：
7.4
通讯作者：
Zhang DD
中科院分区：
文献类型：
--
作者：
Jiang T;Harder B;Rojo de la Vega M;Wong PK;Chapman E;Zhang DD
Nrf2-Keap1-ARE途径是一个氧化还原和异种生物敏感的信号轴，通过诱导细胞保护基因来保护细胞免受氧化应激、环境毒物和有害化学物质的伤害。为了执行严格的调控，细胞投入大量的能量来维持Nrf2通路，以确保在细胞损伤时迅速诱导，并在损伤减轻后迅速恢复到基础水平。由于Nrf2转录程序的保护作用，该途径的受控激活已被认为是一种化学预防手段。另一方面，由于控制Nrf2降解的基因的体细胞突变，Nrf2的结构性激活促进了癌症的发生，并赋予癌细胞化疗耐药性。自噬是一种大宗蛋白质降解过程，是另一个受到严格调控的复杂细胞过程，其功能是作为细胞质量控制系统来移除受损的蛋白质或细胞器。低的细胞营养水平也可以激活自噬，自噬通过降解大分子来提供营养来恢复代谢的动态平衡。最近，这两条细胞通路通过p62(一种自噬适配器蛋白)和Keap1(CUL3E3泛素连接酶的Nrf2底物接头)之间的直接相互作用而被证明是交叉的。自噬的失调被证明以p62依赖的方式导致Nrf2激活延长。在这篇综述中，我们将讨论在解剖这两条通路的交叉点以及延长Nrf2激活的潜在促肿瘤作用方面所取得的进展。
The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation.