The NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops

NRF2 is a well-known, master transcription factor (TF) of oxidative and xenobiotic stress responses. Recent studies uncovered an even wider regulatory role of NRF2 influencing carcinogenesis, inflammation and neurodegeneration. Prompted by these advances here we present a systems-level resource for NRF2 interactome and regulome that includes 289 protein–protein, 7469 TF–DNA and 85 miRNA interactions. As systems-level examples of NRF2-related signaling we identified regulatory loops of NRF2 interacting proteins (e.g., JNK1 and CBP) and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The presented network and the uncovered regulatory loops may facilitate the development of efficient, NRF2-based therapeutic agents.

► We present a systems-level resource for NRF2 studies. ► Following manual curation we found 79 NRF2 interactors and 29 NRF2 target genes. ► We predict 116 novel NRF2 interactors from domain-domain, domain–motif information. ► We find 34 transcription factors and 85 miRNAs capable to directly regulate NRF2. ► We highlight 35 NRF2-regulated TFs influencing 63 miRNAs that down-regulate NRF2.