Stress sensing and protein degradation mechanism of oxidative stress sensor Keapl

转录因子Nrf2是编码2相解毒酶和抗氧化应激蛋白的基因的主要调节因子，以响应亲电试剂和氧化应激。在缺乏这些刺激的情况下，Nrf2由于其被Keap 1保留在细胞质中并通过蛋白酶体系统快速降解而失活。在本研究中，我们确定了Nrf2通过DLG和ETGE模体以双位点分子识别方式与Keap 1同源二聚体复合物结合。似乎这种关联允许有效的泛素转移到Nrf2的赖氨酸残基，最终导致Nrf2在非应激条件下的快速降解。生化研究表明，DLG基序与Keapl的结合比ETGE基序弱。因此，我们假设氧化应激引起Keap1的构象变化，导致DLG和Keap1之间的弱结合被破坏。氧化应激对Nrf2的稳定作用可能是应激介导Nrf2活化的自然途径之一。

Transcription factor Nrf2 is a major regulator of genes encoding phase 2 detoxifying enzymes andanti-oxidant stress proteins in response to electrophilic agents and oxidative stress. In the absence of suchstimuli, Nrf2 is inactive owing to its cytoplasmic retention by Keap 1 and rapid degradation through theproteasome system. In this research, we identified that Nrf2 associates with Keap 1 homodimer complexthrough the DLG and ETGE motifs in the two site molecular recognition manner. It seems that thisassociation allows for the efficient ubiquitin transfer to lysine residues of Nrf2, ultimately resulting in therapid degradation of Nrf2 under unstressed conditions. Biochemical study showed that association ofDLG motif with Keapl is weaker that that of ETGE motif. Therefore we hypothesize that oxidative stressprovokes the conformational change of Keapl, resulting in disruption of the weak binding between DLGand Keap1. This disruption might stabilize and activate Nrf2 because of the inhibited ubiquitination.This stabilization of Nrf2 by oxidative stress seems to be one of the nature way of stress-mediatedactivation of Nrf2.