Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation
Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation
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DOI：
10.1074/jbc.m113.540633
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发表时间：
2014-05-30
影响因子：
4.8
通讯作者：
Lastres-Becker, Isabel
中科院分区：
文献类型：
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作者：
Cuadrado, Antonio;Martin-Moldes, Zaira;Lastres-Becker, Isabel
背景：RAC 1是Rho家族的小G蛋白，其激活转录因子NF-B以引起炎症反应。结果：我们发现RAC 1还诱导NRF 2/ARE通路，其在术语中阻断RAC 1依赖的NF-B活化。结论：RAC 1通过调节促炎转录因子NF-B和抗氧化转录因子NRF 2的活性来调节炎症反应。重要性：对RAC 1的治疗干预可以帮助调节促炎和抗炎过程。小的GTdR蛋白RAC 1通过激活复杂的程序参与先天免疫，该程序包括细胞骨架重塑、趋化性、NADPH氧化酶的激活和基因表达的调节。然而，其在调节转录特征中的作用，即在术语中控制细胞炎症谱还没有很好地定义。在这里，我们研究了RAC 1和转录因子NRF 2（核因子红细胞2相关因子2），抗氧化反应的主调节器之间的功能和机制连接。脂多糖和组成型活性RAC 1（Q61 L）突变体通过激活NRF 2诱导抗氧化酶血红素加氧酶-1（HO-1）。KEAP 1不敏感的NRF 2突变体的使用表明，RAC 1对NRF 2的调节是KEAP 1不依赖的。有趣的是，NRF 2过表达抑制，而NRF 2的显性负突变体加剧了核因子-B（NF-B）的RAC 1依赖性激活，这表明NRF 2对NF-B通路具有拮抗作用。此外，我们发现RAC 1通过NF-B来诱导NRF 2，因为与对照细胞相比，表达导致NF-B降解的IB显性负突变体或使用p65-NF-B缺陷细胞表现出较低的NRF 2蛋白水平和基本受损的NRF 2特征。相反，NRF 2缺陷细胞显示p65-NF-B蛋白水平增加，尽管mRNA水平保持不变，表明翻译后改变。我们的研究结果表明，通过NF-B和NRF 2之间的串扰RAC 1炎症通路的调制的新机制。
Background: RAC1 is a small G-protein of the Rho family that activates the transcription factor NF-B to elicit an inflammatory response. Results: We have found that RAC1 also induces the NRF2/ARE pathway, which in term blocks RAC1-dependent NF-B activation. Conclusion: RAC1 modulates inflammation by coordinating the activity of pro-inflammatory NF-B and anti-oxidant NRF2 transcription factors. Significance: Therapeutic intervention on RAC1 could help modulate pro- and anti-inflammatory processes.The small GTPase protein RAC1 participates in innate immunity by activating a complex program that includes cytoskeleton remodeling, chemotaxis, activation of NADPH oxidase, and modulation of gene expression. However, its role in regulating the transcriptional signatures that in term control the cellular inflammatory profiles are not well defined. Here we investigated the functional and mechanistic connection between RAC1 and the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2), master regulator of the anti-oxidant response. Lipopolysaccharide and constitutively active RAC1(Q61L) mutant induced the anti-oxidant enzyme heme-oxygenase-1 (HO-1) through activation of NRF2. The use of KEAP1-insensitive NRF2 mutants indicated that RAC1 regulation of NRF2 is KEAP1-independent. Interestingly, NRF2 overexpression inhibited, whereas a dominant-negative mutant of NRF2 exacerbated RAC1-dependent activation of nuclear factor-B (NF-B), suggesting that NRF2 has an antagonistic effect on the NF-B pathway. Moreover, we found that RAC1 acts through NF-B to induce NRF2 because either expression of a dominant negative mutant of IB that leads to NF-B degradation or the use of p65-NF-B-deficient cells demonstrated lower NRF2 protein levels and basally impaired NRF2 signature compared with control cells. In contrast, NRF2-deficient cells showed increased p65-NF-B protein levels, although the mRNA levels remain unchanged, indicating post-translational alterations. Our results demonstrate a new mechanism of modulation of RAC1 inflammatory pathway through a cross-talk between NF-B and NRF2.