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A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation

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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., Ponsford, A.H., Boyd, J., Woodsmith, J., Stelzl, U., Wanker, E., Harper, N., 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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