Proximity proteomic analysis of the NRF family reveals the Parkinson’s disease protein ZNF746/PARIS as a co-complexed repressor of NRF2

Author:

LaPak Kyle M.1ORCID,Saeidi Soma1,Bok Ilah1ORCID,Wamsley Nathan T.1,Plutzer Isaac B.1ORCID,Bhatt Dhaval P.1ORCID,Luo Jingqin2ORCID,Ashrafi Ghazaleh13ORCID,Ben Major M.1ORCID

Affiliation:

1. Department of Cell Biology and Physiology, Washington University, St. Louis, MO 63110, USA.

2. Division of Public Health Sciences, Department of Surgery, WUSM and Siteman Cancer Center Biostatistics and Qualitative Research Shared Resource, Washington University, St. Louis, MO 63110, USA.

3. Department of Genetics, Washington University, St. Louis, MO 63110, USA.

Abstract

The nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor activates cytoprotective and metabolic gene expression in response to various electrophilic stressors. Constitutive NRF2 activity promotes cancer progression, whereas decreased NRF2 function contributes to neurodegenerative diseases. We used proximity proteomic analysis to define protein networks for NRF2 and its family members NRF1, NRF3, and the NRF2 heterodimer MAFG. A functional screen of co-complexed proteins revealed previously uncharacterized regulators of NRF2 transcriptional activity. We found that ZNF746 (also known as PARIS), a zinc finger transcription factor implicated in Parkinson’s disease, physically associated with NRF2 and MAFG, resulting in suppression of NRF2-driven transcription. ZNF746 overexpression increased oxidative stress and apoptosis in a neuronal cell model of Parkinson’s disease, phenotypes that were reversed by chemical and genetic hyperactivation of NRF2. This study presents a functionally annotated proximity network for NRF2 and suggests a link between ZNF746 overexpression in Parkinson’s disease and inhibition of NRF2-driven neuroprotection.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

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