Niture Suryakant K, Jaiswal Anil K
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201.
J Biol Chem. 2009 May 15;284(20):13856-13868. doi: 10.1074/jbc.M808084200. Epub 2009 Mar 11.
Nrf2-mediated coordinated induction of a battery of defensive genes is a critical mechanism in cellular protection and survival. INrf2 (Keap1), an inhibitor of Nrf2, functions as an adaptor for Cul3 Rbx1-mediated degradation of Nrf2. A majority of the INrf2/Cul3 Rbx1 complex is localized in the cytosol that degrades cytosolic Nrf2. However, 10-15% of INrf2 is also localized inside the nucleus. INrf2 does not contain a defined nuclear import signal, and the mechanism of nuclear import and its function inside the nucleus remain obscure. Present studies demonstrate that the DGR region of INrf2 is required for nuclear import of INrf2. Studies also demonstrate that Cul3 and Rbx1 are also imported inside the nucleus in complex with INrf2. Interestingly, Nrf2 and prothymosin-alpha both bind to the DGR region of INrf2. However, it is prothymosin-alpha and not Nrf2 that mediates nuclear import of INrf2/Cul3 Rbx1 complex. Antioxidant treatment increases nuclear import of INrf2/Cul3 Rbx1 complex. The INrf2/Cul3 Rbx1 complex inside the nucleus exchanges prothymosin-alpha with Nrf2, resulting in degradation of Nrf2. These results led to the conclusion that prothymosin-alpha-mediated nuclear import of INrf2/Cul3 Rbx1 complex leads to ubiquitination and degradation of Nrf2 inside the nucleus presumably to regulate nuclear level of Nrf2 and rapidly switch off the activation of Nrf2 downstream gene expression.
Nrf2介导的一系列防御基因的协同诱导是细胞保护和存活的关键机制。INrf2（Keap1）作为Nrf2的抑制剂，充当Cul3 Rbx1介导的Nrf2降解的衔接子。大多数INrf2/Cul3 Rbx1复合物定位于细胞质中，可降解细胞质中的Nrf2。然而，10-15%的INrf2也定位于细胞核内。INrf2不包含明确的核输入信号，其核输入机制及其在细胞核内的功能仍不清楚。目前的研究表明，INrf2的DGR区域是INrf2核输入所必需的。研究还表明，Cul3和Rbx1也与INrf2形成复合物进入细胞核。有趣的是，Nrf2和前胸腺素α都与INrf2的DGR区域结合。然而，介导INrf2/Cul3 Rbx1复合物核输入的是前胸腺素α而不是Nrf2。抗氧化剂处理可增加INrf2/Cul3 Rbx1复合物的核输入。细胞核内的INrf2/Cul3 Rbx1复合物将前胸腺素α与Nrf2交换，导致Nrf2降解。这些结果得出结论，前胸腺素α介导的INrf2/Cul3 Rbx1复合物核输入导致细胞核内Nrf2的泛素化和降解，大概是为了调节Nrf2的核水平并迅速关闭Nrf2下游基因表达的激活。
