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Proximal proteomics connects NRF2 suppression to ZNF746/PARIS-driven oxidative stress and apoptosis in Parkinson’s disease

ABSTRACT: The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. In disease, constitutive NRF2 activity promotes cancer progression while decreased NRF2 function contributes to neurodegenerative diseases. In contrast to the regulation of NRF2 protein stability in the cytoplasm, co-complexed proteins that govern NRF2 activity on chromatin are less clear. Using biotin proximity proteomics, we report networks for NRF2 and its family members NRF1, NRF3 and the NRF2 heterodimer MAFG. We found that the Parkinson’s disease zinc finger transcription factor ZNF746 (PARIS) physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 expression increased oxidative stress and apoptosis, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests that ZNF746 overexpression in Parkinson’s disease directly inhibits NRF2-driven neuroprotection

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Kidney

DISEASE(S): Disease Free

SUBMITTER: Kyle LaPak

LAB HEAD: Michael Ben Major

PROVIDER: PXD043182 | Pride | 2023-12-18

REPOSITORIES: Pride

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