PXD036607 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | REV-ERBα-UPS signaling pathway study to prevent Myocardial ischemia-reperfusion injury |
Description | Myocardial ischemia-reperfusion injury (MIRI) is a major threat to heart functional integrity and pharmacological means to achieve cardioprotection are sorely needed. The sequential hypoxic/normoxic status of the cardiac tissue triggers life-threatening damages through the activation of multiple intra-cellular pathways. Heart tolerance to MIRI varies according to a day-night cycle and is regulated by components of the molecular clock such as the transcriptional repressor and nuclear receptor REV-ERBα. Timed REV-ERBα antagonism alleviates sensitivity to myocardial infarction in mice. Here we show that timed administration of digoxin is cardioprotective by triggering REV-ERBα protein degradation. Kinomics and transcriptomic assays revealed that in several cardiomyocyte cellular models, digoxin and other cardiotonic steroids induced multiple signaling pathways. Pharmacological inhibition and knockdown approaches revealed that inhibition of the Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation, which was fully prevented upon proteasome inhibition. REV-ERBα is increasingly ubiquitinylated in digoxin-treated cells, and its degradation depends on its ability to bind its natural ligand, heme. In unchallenged conditions, the proteasomal degradation of REV-ERBα is controlled by several known (HUWE1, FXW7, SIAH2) or novel (CBL, UBE4B)E3 ubiquitin ligases. Only SIAH2 together with the proteasome subunit PSMB5 were found tocontribute to the digoxin-induced degradation of REV-ERBα. Taken together, these results show that controlling REV-ERBα proteostasis is an appealing cardioprotective strategy, and bring further support to the rationale, timed use of CTS in prophylactic cardiac preconditioning to MIRI. |
HostingRepository | PRIDE |
AnnounceDate | 2022-09-13 |
AnnouncementXML | Submission_2022-09-13_10:00:02.527.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Agnès Hovasse |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-09-12 02:23:59 | ID requested | |
⏵ 1 | 2022-09-13 10:00:02 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Human, REV-ERBα, U2OS, HepG2, RIME |
Contact List
Agnes Hovasse |
contact affiliation | Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, UMR 7178, Université de Strasbourg, CNRS, 67087 Strasbourg, France; Infrastructure Nationale de Protéomique ProFI − FR2048 CNRS, 67087 Strasbourg, France |
contact email | ahovasse@unistra.fr |
lab head | |
Agnès Hovasse |
contact affiliation | Laboratoire de Spectrométrie de Masse BioOrganique, University of Strasbourg, CNRS, Institut Pluridisciplinaire Hubert Curien, UMR 7178 |
contact email | ahovasse@unistra.fr |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD036607
- Label: PRIDE project
- Name: REV-ERBα-UPS signaling pathway study to prevent Myocardial ischemia-reperfusion injury