CR6-interacting factor 1 (CRIF1) regulates NF-E2-related factor 2 (NRF2) protein stability by proteasome-mediated degradation.
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.
Kang
Hyo Jin
HJ
Departments of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Hong
Young Bin
YB
Kim
Hee Jeong
HJ
Bae
Insoo
I
D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005609:Free Radicals; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000737:chemistry
D018797:Cell Cycle Proteins; D005609:Free Radicals; C476586:GADD45GIP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex