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Ubiquitylation-omics analysis on WWP2 overexpressed mouse tubular epithelial cells (MPTCs)

ABSTRACT: WWP2 is a E3 ubiquitin ligase which may be implicated in multiple cellular event. WWP2 expressed in the kidneys and its pathological role remain to be elucidated. We performed this ubiquitylation omics analysis on renal tubular epithelial cells which overexpressd WWP2 to study WWP2's potential ubiquitylation substrate in the kidneys.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Ran You

LAB HEAD: Aihua Zhang

PROVIDER: PXD048540 | Pride | 2025-06-09

REPOSITORIES: Pride

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			Action	DRS
	S9707LPUbB1_MFL_Slot1-19_1_3713.d.zip	Other
	S9707LPUbB1_MV_Slot1-18_1_3711.d.zip	Other
	checksum.txt	Txt
	txt.zip	Other

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Publications

WWP2 deletion aggravates acute kidney injury by targeting CDC20/autophagy axis.

You Ran R Li Yanwei Y Jiang Yuteng Y Hu Dandan D Gu Menglei M Zhou Wei W Zhang Shengnan S Bai Mi M Yang Yunwen Y Zhang Yue Y Huang Songming S Jia Zhanjun Z Zhang Aihua A

Journal of advanced research 20240622

<h4>Introduction</h4>Acute kidney injury (AKI) is associated with high morbidity and mortality rates. The molecular mechanisms underlying AKI are currently being extensively investigated. WWP2 is an E3 ligase that regulates cell proliferation and differentiation. Whether WWP2 plays a regulatory role in AKI remains to be elucidated.<h4>Objectives</h4>We aimed to investigate the implication of WWP2 in AKI and its underlying mechanism in the present study.<h4>Methods</h4>We utilized renal tissues f ...[more]

PMID: 38909885

Similar Datasets

Quantitative proteinomics on WWP2 overexpressed human tubular epithelial cells HK-2

Project description:WWP2 is a E3 ligase which regulates multiple cellular events, such as stress response, differentiation. WWP2 played physiological role in the distal tubules of the kidneys. Whether WWP2 regulated pathophysiological rol in the proximal tubules is unclear. In the present study, we stably overexpressed WWP2 using lenti-viral infection in the human tubular epithelial cells, HK-2, and performed proteinomics analysis to explore WWP2's potential substrates.

2025-06-09 | PXD048622 | Pride

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

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 [ChIP-Seq]

2024-05-19 | GSE267765 | GEO

WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

Project description: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.

2022-10-25 | GSE198003 | GEO

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

2024-02-05 | GSE241503 | 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

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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

| PRJNA540306 | ENA

WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

Project description:WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

| PRJNA813315 | ENA