NFE2L2 translocates from cytosol to nucleoplasm

Upon activation by electrophiles or reactive oxygen species Nuclear factor erythroid 2-related (NFE2L2, NRF2) accumulates in the nucleus. The mechanism by which this translocation occurs is not entirely elucidated. NFE2L2 possess two functional nuclear localization signals (NLS) one near the N-terminal region (murine NFE2L2 42-53 aa) and the other (residues 587-593) in the C-terminal region which may function in the nuclear import. It has also been demonstrated that importins might be involved in the nuclear translocation of NFE2L2. NFE2L2 associates especially with importin alpha 5 and beta 1 (Theodore et al. 2008). Nuclear import of NFE2L2 has been shown to be stimulated downstream of active PI3K signaling (Joung et al, 2007; Li et al, 2006; Martin et al, 2004). Similarly, activation of the NFE2L2 pathway has been observed downstream of some oncogenes (Best et al, 2021; Tang et al, 2021; Mitsuishi et al, 2012; De Nicola et al, 2011; Wakabayashi et al, 2014; reviewed in He et al, 2020; Kitamura and Motohashi, 2018). NFE2L2 contributes to oncogenesis through metabolic reprogramming to support proliferation and through enhanced detoxification and antioxidation capabilities (reviewed in He et al, 2020; Kitamura and Motohashi, 2018). Activation of the PI3K pathway through inactivation of PTEN and KEAP1 increases the levels of T308 phosphorylated AKT, and promotes the nuclear accumulation of NFE2L2, stimulating expression of target genes (Mitsuishi et al, 2012; Best et al, 2021).

在亲电试剂或活性氧物种的激活下，核因子红细胞2相关蛋白（NFE2L2，NRF2）在细胞核中累积。此蛋白转移的机制尚未完全阐明。NFE2L2拥有两个功能性的核定位信号（NLS），一个位于N端区域（小鼠NFE2L2的42-53位氨基酸），另一个位于C端区域（氨基酸残基587-593），可能参与核输入过程。已有研究表明，核输入因子可能参与NFE2L2的核转移。NFE2L2尤其与核输入因子α5和β1（Theodore et al. 2008）相关联。NFE2L2的核输入已被证明在活化的PI3K信号通路下游被刺激（Joung et al, 2007; Li et al, 2006; Martin et al, 2004）。类似地，NFE2L2途径的激活已在某些癌基因下游观察到（Best et al, 2021; Tang et al, 2021; Mitsuishi et al, 2012; De Nicola et al, 2011; Wakabayashi et al, 2014；参见He et al, 2020; Kitamura and Motohashi, 2018的综述）。NFE2L2通过代谢重编程以支持增殖，并通过增强的解毒和抗氧化能力，参与肿瘤发生（参见He et al, 2020; Kitamura and Motohashi, 2018的综述）。通过PTEN和KEAP1的失活激活PI3K通路，可增加T308磷酸化AKT的水平，并促进NFE2L2的核累积，刺激靶基因的表达（Mitsuishi et al, 2012; Best et al, 2021）。