CR6-interacting factor 1 (CRIF1) regulates NF-E2-related factor 2 (NRF2) protein stability by proteasome-mediated degradation.
CR6-interacting factor 1 (CRIF1) regulates NF-E2-related factor 2 (NRF2) protein stability by proteasome-mediated degradation.
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DOI：
10.1074/jbc.m109.084590
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发表时间：
2010-07-09
期刊：
影响因子：
--
通讯作者：
Bae I
中科院分区：
文献类型：
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作者：
Kang HJ;Hong YB;Kim HJ;Bae I
氧化应激产生的自由基会造成损害，从而导致许多慢性疾病。哺乳动物细胞通过增加受NRF2调控的细胞保护性II期基因的转录来应对这种损伤。此前已有研究表明，氧化应激后NRF2蛋白水平升高是因为其负调节因子KEAP1在氧化应激过程中失去了结合NRF2并导致其蛋白酶体介导的降解的能力。在这里，我们展示了CRIF1，一种以前被称为细胞周期调节因子和转录辅助因子的蛋白质，也能够负调控NRF2蛋白的稳定性。然而，与KEAP1仅在正常还原条件下调控NRF2稳定性不同，CRIF1在还原和氧化应激条件下均调控NRF2稳定性及其靶基因表达。因此，CRIF1-NRF2相互作用及其后果是氧化还原无关的。此外，我们发现，与KEAP1（仅与NRF2的N端区域相互作用）不同，CRIF1与NRF2的N端和c端区域都有物理相互作用，并促进NRF2泛素化和随后的蛋白酶体介导的NRF2蛋白降解。
Free radicals generated by oxidative stress cause damage that can contribute to numerous chronic diseases. Mammalian cells respond to this damage by increased transcription of cytoprotective phase II genes, which are regulated by NRF2. Previously, it has been shown that NRF2 protein levels increase after oxidative stress because its negative regulator, KEAP1, loses its ability to bind NRF2 and cause its proteasome-mediated degradation during oxidative stress. Here, we show that CRIF1, a protein previously known as cell cycle regulator and transcription cofactor, is also able to negatively regulate NRF2 protein stability. However, in contrast to KEAP1, which regulates NRF2 stability only under normal reducing conditions, CRIF1 regulates NRF2 stability and its target gene expression under both reducing and oxidative stress conditions. Thus, CRIF1-NRF2 interactions and their consequences are redox-independent. In addition, we found that CRIF1, unlike KEAP1 (which only interacts with N-terminal region of NRF2), physically interacts with both N- and C-terminal regions of NRF2 and promotes NRF2 ubiquitination and subsequent proteasome-mediated NRF2 protein degradation.