PXD016312

PXD016312 is an original dataset announced via ProteomeXchange.

Title	Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease
Description	Mitochondrial dysfunction is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed mitochondrial homeostasis in cystic cells remain elusive. In the present study, we identify impaired activity of NRF2 antioxidant pathway as a driver mechanism for mitochondrial dysfunction and ADPKD progression. Using a quantitative proteomic approach, we find that NRF2 antioxidant pathway is suppressed in ADPKD kidneys. In a cohort of ADPKD patients, reactive oxygen species (ROS) levels are frequently elevated, and the increased ROS levels inversely correlates with decreased NRF2 expression and positively correlates with disease severity. Genetic deletion of NRF2 increases ROS generation and promotes cyst growth in an orthologous ADPKD mouse model, while pharmacological induction of NRF2 reduces ROS levels and retards cystogenesis and disease progression. Mechanistically, NRF2 activates its antioxidant target genes mainly through remodeling enhancer landscapes. The activation domain of NRF2 forms phase-separated condensates with MED16, a Mediator complex subunit in vitro, and NRF2 is required for optimal Mediator recruitment to target genomic sites in vivo. Taken together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase-separation mechanism, and that activation of NRF2 represents a promising strategy for restoring mitochondrial homeostasis and combatting ADPKD.
HostingRepository	PRIDE
AnnounceDate	2021-12-12
AnnouncementXML	Submission_2021-12-12_15:21:01.154.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yongzhan Sun
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-18 01:41:47	ID requested
⏵ 1	2021-12-12 15:21:01	announced

Lu Y, Sun Y, Liu Z, Lu Y, Zhu X, Lan B, Mi Z, Dang L, Li N, Zhan W, Tan L, Pi J, Xiong H, Zhang L, Chen Y, Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease. Sci Transl Med, 12(554):(2020) [pubmed]

submitter keyword: mouse, kidney, LC-MSMS, ADPKD

Yupeng Chen
contact affiliation	2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
contact email	ychen@tmu.edu.cn
lab head
Yongzhan Sun
contact affiliation	Tianjin Medical University
contact email	sunyongzhan@tmu.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016312
     1. Label: PRIDE project
     2. Name: Nrf2-mediated enhancer activation via phase separation ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease