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JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

ABSTRACT: JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

PROVIDER: PRJNA1172292 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30972002_1.fastq.gz	Fastqsanger.gz
	SRR30972002_2.fastq.gz	Fastqsanger.gz
	SRR30972003_1.fastq.gz	Fastqsanger.gz
	SRR30972003_2.fastq.gz	Fastqsanger.gz
	SRR30972004_1.fastq.gz	Fastqsanger.gz

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JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

Project description:Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. Here, we identify the deubiquitinating enzyme JOSD2 as a protective factor and investigate its molecular mechanism in Ang II-induced vascular remodeling. Firstly, we found that JOSD2 was up-regulated in aortic smooth muscle cells but not endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by VSMC-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated the fibrosis, proliferation, and migration induced by Ang II in vascular smooth muscle cells (VSMCs), while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to removed K48-linked Ub chains of SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 maybe a novel and potential therapeutic target for hypertensive vascular remodeling.

2024-10-18 | GSE279358 | GEO

JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7

2024-10-10 | PXD056674 | Pride

USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7.

Project description:The amplitude of transforming growth factor-β (TGF-β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-β signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-β receptor complex for ubiquitin-mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-β rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin-mediated turnover of SMAD7. Conversely, knockdown of USP26 rapidly degrades SMAD7 resulting in TGF-β receptor stabilization and enhanced levels of p-SMAD2. Clinically, loss of USP26 correlates with high TGF-β activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF-β pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.

| S-EPMC5412796 | biostudies-literature

Prostate-specific Oncogene OTUD6A Promotes Prostatic Tumorigenesis via Deubiquitinating and Stabilizing c-Myc

Project description:Prostate-specific Oncogene OTUD6A Promotes Prostatic Tumorigenesis via Deubiquitinating and Stabilizing c-Myc

| PRJNA784264 | ENA

Endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3

Project description:Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. In this study, we investigated the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We identified upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and showed OTUD1 deletion attenuated vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravated these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 was identified as a substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. We found OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulate the transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reversed OTUD1-promoted vascular remodeling. Our findings demonstrate endothelial OTUD1 promoted Ang II-induced vascular remodeling by deubiquitinating SMAD3. This study identified SMAD3 as a target of OTUD1 and indicates OTUD1 as a potential therapeutic target for the diseases related to vascular remodeling.

2022-12-24 | GSE217304 | GEO

USP26 regulates TGF-β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma.

Project description:Comment on "USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7" by Kit Leng Lui et al.

| S-EPMC6945060 | biostudies-literature

USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

Project description:Tumour suppressor p53 levels in the cell are tightly regulated by controlled degradation through ubiquitin ligases including Mdm2, COP1, Pirh2, and ARF-BP1. The ubiquitination process is reversible via deubiquitinating enzymes, such as ubiquitin-specific peptidases (USPs). In this study, we identified ubiquitin-specific peptidase 4 (USP4) as an important regulator of p53. USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels. Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation. Compared with wild-type mouse embryonic fibroblasts (MEFs), Usp4-/- MEFs exhibited retarded growth, premature cellular senescence, resistance to oncogenic transformation, and hyperactive DNA damage checkpoints, consistent with upregulated levels and activity of p53 in the absence of USP4. Finally, we showed that USP4 is overexpressed in several types of human cancer, suggesting that USP4 is a potential oncogene.

| S-EPMC3117646 | biostudies-literature

Endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3

2022-12-24 | PXD037926 | Pride

Prostate-specific Oncogene OTUD6A Promotes Prostatic Tumorigenesis via Deubiquitinating and Stabilizing c-Myc

Project description:In this study, we found that OTUD6A is a physiological deubiquitinase for c-Myc in prostate cancer setting and promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein. Moreover, knockout of Otud6a in mice retarded the prostatic tumorigenesis in Hi-Myc prostate cancer mice model

2022-01-01 | GSE189716 | GEO

Response to: USP26 regulates TGF-β signalling by deubiquitinating and stabilizing SMAD7; not applicable in glioblastoma.

Project description: Not available

| S-EPMC6944904 | biostudies-literature