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| Item Type: | Article |
|---|---|
| Title: | A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation |
| Creators Name: | Poh, J. and Ponsford, A.H. and Boyd, J. and Woodsmith, J. and Stelzl, U. and Wanker, E. and Harper, N. and MacEwan, D. and Sanderson, C.M. |
| Abstract: | NRF2 (NFE2L2) is a cytoprotective transcription factor associated with >60 human diseases, adverse drug reactions and therapeutic resistance. To provide insight into the complex regulation of NRF2 responses, 1,962 predicted NRF2-partner interactions were systematically tested to generate an experimentally defined high-density human NRF2 interactome. Verification and conditional stratification of 46 new NRF2 partners was achieved by co-immunoprecipitation and the novel integration of quantitative data from dual luminescence-based co-immunoprecipitation (DULIP) assays and live-cell fluorescence cross-correlation spectroscopy (FCCS). The functional impact of new partners was then assessed in genetically edited loss-of-function (NRF2(-/-)) and disease-related gain-of-function (NRF2(T80K) and KEAP1(-/-)) cell-lines. Of the new partners investigated >77% (17/22) modified NRF2 responses, including partners that only exhibited effects under disease-related conditions. This experimentally defined binary NRF2 interactome provides a new vision of the complex molecular networks that govern the modulation and consequence of NRF2 activity in health and disease. |
| Keywords: | NRF2/NFE2L2, KEAP1, Protein Interaction Network (PIN), Fluorescence Cross-Correlation Spectroscopy (FCCS), Dual Luminescence-Based Co-Immunoprecipitation (DULIP), Human Disease Network, Binary Interactome |
| Source: | Redox Biology |
| ISSN: | 2213-2317 |
| Publisher: | Elsevier |
| Volume: | 37 |
| Page Range: | 101686 |
| Date: | October 2020 |
| Official Publication: | https://doi.org/10.1016/j.redox.2020.101686 |
| PubMed: | View item in PubMed |
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