PXD036607

PXD036607 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-12 02:23:59	ID requested
⏵ 1	2022-09-13 10:00:02	announced

Dataset with its publication pending

submitter keyword: Human, REV-ERBα, U2OS, HepG2, RIME

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

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PRIDE project URI

• PRIDE
  1. PXD036607
     1. Label: PRIDE project
     2. Name: REV-ERBα-UPS signaling pathway study to prevent Myocardial ischemia-reperfusion injury