PXD012121

PXD012121 is an original dataset announced via ProteomeXchange.

Title	The auophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages
Description	Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.
HostingRepository	PRIDE
AnnounceDate	2019-06-11
AnnouncementXML	Submission_2019-06-11_00:23:49.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jarne Pauwels
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2018-12-19 05:38:44	ID requested
⏵ 1	2019-06-11 00:23:50	announced

Mylka V, Deckers J, Ratman D, De Cauwer L, Thommis J, De Rycke R, Impens F, Libert C, Tavernier J, Vanden Berghe W, Gevaert K, De Bosscher K, The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages. Autophagy, 14(12):2049-2064(2018) [pubmed]

submitter keyword: Autophagy

autophagy receptors

CpdA

glucocorticoids

inflammation

NFE2L2/NRF2

SQSTM1/p62

Karolien De Bosscher
contact affiliation	Receptor Research Laboratories, Nuclear Receptor Lab, Ghent University, Ghent, Belgium; cDepartment of Biochemistry, VIB-UGent Center for Medical Biotechnology, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium
contact email	karolien.debosscher@vib-ugent.be
lab head
Jarne Pauwels
contact affiliation	VIB-Ugent
contact email	jarne.pauwels@vib-ugent.be
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/2019/06/PXD012121

PRIDE project URI

• PRIDE
  1. PXD012121
     1. Label: PRIDE project
     2. Name: The auophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages