PMID- 38085818
OWN - NLM
STAT- MEDLINE
DCOM- 20231216
LR  - 20240425
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Print)
IS  - 1945-0877 (Linking)
VI  - 16
IP  - 815
DP  - 2023 Dec 12
TI  - Proximity proteomic analysis of the NRF family reveals the Parkinson's disease 
      protein ZNF746/PARIS as a co-complexed repressor of NRF2.
PG  - eadi9018
LID - 10.1126/scisignal.adi9018 [doi]
AB  - 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.
FAU - LaPak, Kyle M
AU  - LaPak KM
AUID- ORCID: 0000-0002-7571-4222
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Saeidi, Soma
AU  - Saeidi S
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Bok, Ilah
AU  - Bok I
AUID- ORCID: 0000-0001-8958-5161
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Wamsley, Nathan T
AU  - Wamsley NT
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Plutzer, Isaac B
AU  - Plutzer IB
AUID- ORCID: 0000-0002-9370-7763
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Bhatt, Dhaval P
AU  - Bhatt DP
AUID- ORCID: 0000-0002-2037-9332
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
FAU - Luo, Jingqin
AU  - Luo J
AUID- ORCID: 0000-0003-2759-3072
AD  - 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.
FAU - Ashrafi, Ghazaleh
AU  - Ashrafi G
AUID- ORCID: 0000-0001-7480-0826
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
AD  - Department of Genetics, Washington University, St. Louis, MO 63110, USA.
FAU - Ben Major, M
AU  - Ben Major M
AUID- ORCID: 0000-0002-6753-8513
AD  - Department of Cell Biology and Physiology, Washington University, St. Louis, MO 
      63110, USA.
LA  - eng
GR  - R01 CA216051/CA/NCI NIH HHS/United States
GR  - T32 CA009547/CA/NCI NIH HHS/United States
GR  - R01 CA244236/CA/NCI NIH HHS/United States
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
GR  - R35 GM147222/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20231212
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Repressor Proteins)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Co-Repressor Proteins)
RN  - 0 (ZNF746 protein, human)
SB  - IM
MH  - Humans
MH  - *Parkinson Disease/genetics/metabolism
MH  - Repressor Proteins/metabolism
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - Co-Repressor Proteins
MH  - Proteomics
PMC - PMC10760916
MID - NIHMS1952631
COIS- Competing interests: The authors declare that they have no competing interests.
EDAT- 2023/12/12 18:42
MHDA- 2023/12/17 09:43
PMCR- 2024/12/12
CRDT- 2023/12/12 14:03
PHST- 2024/12/12 00:00 [pmc-release]
PHST- 2023/12/17 09:43 [medline]
PHST- 2023/12/12 18:42 [pubmed]
PHST- 2023/12/12 14:03 [entrez]
AID - 10.1126/scisignal.adi9018 [doi]
PST - ppublish
SO  - Sci Signal. 2023 Dec 12;16(815):eadi9018. doi: 10.1126/scisignal.adi9018. Epub 
      2023 Dec 12.