Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

ABSTRACT: Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac remodelling. Recent evidence implicates monocytes/macrophages modulating cardiac fibrosis but targeting these is convoluted, giving their tissue heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis. Here we focus on the role of WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that its myeloid-specific deletion reduces cardiac fibrosis in hypertension-induced NICM. Using the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase driven by Ccl5-expressing Ly6chigh monocytes. Among other cardiac macrophage subtypes, WWP2 dysfunction primarily affects the Ccl5-dependent infiltration and activation of Ly6chigh monocytes, which causes reduced myofibroblast trans-differentiation. WWP2 interacts with IRF7, promoting its non-degradative monoubiquitination, nuclear translocation and transcriptional activity, including upstream Ccl5. Thus, we identify WWP2 as a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE198003 | GEO | 2022/10/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Project description:WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

| PRJNA540306 | ENA

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.

2024-02-05 | GSE241502 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

2024-02-05 | GSE241503 | GEO

Triggering of NOD2 receptor converts inflammatory Ly6Chigh into Ly6Clow monocytes with patrolling properties.

Project description:In the present study, we demonstrate that NOD2 receptor triggering by muramyl dipeptide converts blood inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Muramyl dipeptide administration to Nr4a1-/- mice, which lack Ly6Clow monocytes, and to Ly6Clow-depleted mice leads to the emergence of blood patrolling monocytes expressing phenotypic profile of typical Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Furthermore using intravital microscopy in live animal models of inflammatory diseases, we observed that converted Ly6Chigh monocytes are capable of patrolling the endothelium of blood vessels and their presence contributes to reduce the inflammatory response following muramyl dipeptide injection.

2019-01-14 | GSE101496 | GEO

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Project description:Bulk RNA-seq heart left ventricle data from wild type and WWP2 gene mutant mice (after 28 days of angiotensinII treatment)

2019-07-08 | GSE130468 | GEO

Enzymatic Analysis of WWP2 E3 Ubiquitin Ligase Using Protein Microarrays Identifies Autophagy-Related Substrates

Project description:WWP2 is a HECT E3 ligase that targets protein Lys residues for ubiquitination. As a member of the NEDD4 family of E3 ligases, WWP2 is comprised of an N-terminal C2 domain, four central WW domains, and a C-terminal catalytic HECT domain. The peptide segment between the middle WW domains, the 2,3-linker, can autoinhibit the catalytic domain and this can be relieved by phosphorylation at Tyr369. Several protein substrates of WWP2 have been identified, including the tumor suppressor lipid phosphatase PTEN, but the full substrate landscape and biological functions of WWP2 remain to be elucidated. Here we use protein microarray technology and the activated enzyme phosphomimetic mutant WWP2Y369E to identify potential WWP2 substrates. We identified 31 substrate hits for WWP2Y369E using protein microarrays of which three are the autophagy receptors, NDP52, OPTN, and SQSTM1. These three hits were validated with in vitro and cell-based transfection assays and the Lys ubiquitination sites on these proteins were mapped by mass spectrometry. Among the mapped ubiquitin sites on these autophagy receptors, many were previously identified in studies on the endogenous proteins. WWP2 knockout SH-SH5Y neuroblastoma cells using CRISPR-Cas9 showed a defect in mitophagy in a fashion that could be rescued by WWP2Y369E transfection. These studies suggest that WWP2-mediated ubiquitination of the autophagy receptors NDP52, OPTN, and SQSTM1 may positively contribute to the regulation of autophagy.

2022-05-20 | PXD031703 | Pride

Quantitative Temporal in vivo Proteomics (QTiPs) deciphers the transition of inflammatory CD11b+,Ly6G-,Ly6Chigh myeloid cells into M2-like macrophages

Project description:Phenotypic transition of myeloid cells into distinct lineages in vivo is important in pathogen response. To monitor immune cell phenotype transitions in vivo, we developed a quantitative temporal in vivo proteomics (QTiPs) platform, performing multiplexed (10-plex) tandem-mass-tag (TMT)-based mass spectrometry on sorted cells collected from their in situ microenvironment during infection. We temporally characterized a poorly understood, virus-driven CD11b+,Ly6G-,Ly6Chigh-low myeloid cell population throughout an acute phase of infection in both the site of infection and bone marrow. QTiPs, in combination with phenotypic, functional and metabolic analyses, elucidated a pivotal role for inflammatory CD11b+,Ly6G-,Ly6Chigh-low cells in anti-viral immune response and viral clearance. Most importantly, the highly time-resolved QTiPs dataset showed the transition of CD11b+,Ly6G-,Ly6Chigh-low cells into M2-like macrophages which displayed increased antigen presentation capacities and bioenergetic demands late in infection. Our QTiPs approach precisely captures myeloid cell-macrophage transition in this population, and it is a novel platform for measuring temporospatial proteome transitions in vivo.

2017-08-09 | PXD005064 | Pride

Identification of miR-146a target genes in mouse monocyte subsets

Project description:To gain insight into the mechanisms underlying miR-146a-mediated modulation of Ly6Chigh monocyte function, we compared the expression profiles of Ly6Chigh and Ly6Clow monocytes in miR-146a+/+ (WT) versus miR-146a-/- (KO) conditions.

2019-06-01 | GSE77159 | GEO

Myocardial Infarction accelerates breast cancer progression via innate immune reprogramming (RNA-seq: sham vs LAD ligation)

Project description:Breast cancer patients have increased risk of myocardial infarction (MI), but whether these events impact cancer pathogenesis is not known. In mouse models of breast cancer, MI increased circulating Ly6Chigh monocytes and their recruitment to tumors, accelerating cancer progression and metastasis. Analysis of the bone marrow reservoir revealed that MI epigenetically reprogrammed Ly6Chigh monocytes to an immunosuppressive phenotype that was maintained in monocytes in the circulation and tumor at the transcriptional level. Depletion of Ly6Chigh monocytes abrogated MI-induced cancer progression and increased activated cytotoxic T cells in the tumor. In early-stage breast cancer patients, post-diagnosis incident cardiovascular events, such as MI, increased the risk of recurrence and cancer-specific mortality, highlighting the clinical relevance of our findings. Collectively, our results indicate that MI induces cross-disease communication that accelerates breast cancer progression.

2020-06-11 | GSE147929 | GEO

Ubiquitin ligase WWP2 targets RNA polymerase II in a DNA-PK-dependent transcription shutoff circuitry for DNA repair

Project description:DNA double-strand breaks (DSBs) at RNA polymerase II (RNAPII)-transcribed genes lead to inhibition of transcription. DNA protein kinase (DNA-PK) complex plays a pivotal role in transcription inhibition at DSBs by stimulating proteasome-dependent eviction of RNAPII at these lesions. How DNA-PK triggers RNAPII eviction to inhibit transcription at DSBs remained unclear. Here we show that the HECT E3 ubiquitin ligase WWP2 associates with components of the DNA-PK and RNAPII complexes and is recruited to DSBs at RNAPII-transcribed genes. In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. The lack of WWP2 or expression of non-ubiquitylatable RPB1 abrogates the loading of Non-Homologous End-Joining (NHEJ) factors, including DNA-PK and XRCC4/DNA ligase IV, and impairs DSB repair. These findings suggest that WWP2 operates in a DNA-PK-dependent shut-off circuitry for RNAPII clearance that promotes DSB repair by protecting the NHEJ machinery from collision with the transcription machinery.

2019-03-29 | PXD012606 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data