PXD013640

PXD013640 is an original dataset announced via ProteomeXchange.

Title	Keap-1-mediated S-nitrosylation of NOX4 hampers oxidative damage in endothelium
Description	ABSTRACT Rationale Premature senescence is conducive to aging and cardiovascular diseases. Nrf2 transcription factor, the master orchestrator of adoptive response to cellular stress, has been implicated in regulation of premature senescence in fibroblasts, neural and mesenchymal stem cells by transactivation of antioxidant gene expression. However, as we show here, human primary endothelial cells (ECs) devoid of Nrf2 and murine Nrf2 transcriptional knockout (tKO) aortas are senescent but do not encounter oxidative stress and damage, what contradicts this mechanism. Moreover, a molecular switch between normal, senescent and apoptotic fate remains unknown. Objective To elucidate the mechanism of Nrf2-related premature senescence of vascular system, to understand why Nrf2 deregulation does not cause oxidative stress exclusionary in ECs and to indicate a molecular switch determining ECs fate. Methods and Results Herein we evidence that ECs deficient in Nrf2 protein, or with limited Nrf2 activity in shear stress conditions, exhibit excessive S-nitrosylation of proteins. It is also a characteristic of Nrf2 tKO murine aortas, as determined by biotin switch assay in situ. Mass spectrometry analysis reveals that NOX4 is S-nitrosylated exclusively in ECs devoid of Nrf2. A functional role of S-nitrosylation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage. As a result Nrf2-deficient ECs preserve oxidative balance but are redirected to premature senescence. The same phenotype is seen in Nrf2 tKO aortas. These effects are mediated by Keap1, a direct binding partner of Nrf2 and repressor of its transcriptional activity, remaining in cytoplasm unrestrained by Nrf2. S-nitrosylation, followed by senescence, can also be triggered in smooth muscle cells (SMCs) by EC-derived paracrine induction of iNOS. Conclusions Collectively, Keap1-dependent S-nitrosylation of NOX4 hampers oxidative detriment in ECs with disturbed Nrf2 signaling and may provide defence in the adjacent aortic cells. Overabundance of unrestrained Keap1 in the cytoplasm determines fate of ECs.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:10:39.048.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dominik Cysewski
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-26 01:39:33	ID requested
1	2020-08-12 02:53:45	announced
⏵ 2	2024-10-22 05:10:39	announced	2024-10-22: Updated project metadata.

10.1016/j.redox.2020.101572;

Kopacz A, Kloska D, Targosz-Korecka M, Zapotoczny B, Cysewski D, Personnic N, Werner E, Hajduk K, Jozkowicz A, Grochot-Przeczek A, Keap1 governs ageing-induced protein aggregation in endothelial cells. Redox Biol, 34():101572(2020) [pubmed]

submitter keyword: endothelial cells, S-nitrosylation, Nrf2, NOX4, oxidative stress

Anna Grochot-Przęczek
contact affiliation	Department of Medical Biotechnology Faculty of Biochemistry, Biophysics and Biotechnology Jagiellonian University Gronostajowa 7 30-387 Krakow, Poland
contact email	anna.grochot-przeczek@uj.edu.pl
lab head
Dominik Cysewski
contact affiliation	Medical University of Bialystok
contact email	dominikcysewski@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/08/PXD013640

PRIDE project URI

• PRIDE
  1. PXD013640
     1. Label: PRIDE project
     2. Name: Keap-1-mediated S-nitrosylation of NOX4 hampers oxidative damage in endothelium