USP2 inhibition prevents infection with ACE2- dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA996524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25338771_1.fastq.gz | Fastqsanger.gz | |||
| SRR25338771_2.fastq.gz | Fastqsanger.gz | |||
| SRR25338772_1.fastq.gz | Fastqsanger.gz | |||
| SRR25338772_2.fastq.gz | Fastqsanger.gz | |||
| SRR25338773_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we identified USP2 as a physiological deubiquitinase of ACE2 and USP2 inhibition led to ACE2 protein destruction, thereby preventing infections of coronaviruses that reliant on ACE2
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Project description:Sepsis remains a major cause of death worldwide. The lung is particularly vulnerable, and sepsis‑induced acute lung injury (ALI) carries high mortality. Endothelial glycocalyx degradation is an early event that promotes vascular leakage and inflammation, but the upstream regulators of this process are poorly understood. Here we identify ubiquitin‑specific protease 2 (USP2) as a critical driver of pulmonary endothelial glycocalyx breakdown in sepsis. USP2 expression was markedly upregulated in lung endothelial cells of septic mice and in LPS-stimulated human endothelial cells. Endothelial‑specific Usp2 knockdown protected against cecal ligation and puncture (CLP)‑induced lung injury, vascular leakage, and glycocalyx degradation. Mechanistically, USP2 directly bound to mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, and removed K27‑linked ubiquitin chains at lysine 158, thereby stabilizing MTCH2. MTCH2 was required for USP2‑mediated downregulation of syndecan‑1 (SDC1), a core glycocalyx component, and its silencing rescued SDC1 levels in USP2‑overexpressing cells. Endothelial‑specific Mtch2 knockout mice phenocopied the protective effects of USP2 deficiency, including improved survival, preserved glycocalyx structure, and reduced inflammation. These findings uncover a USP2‑MTCH2 axis that links deubiquitination to glycocalyx integrity in the pulmonary endothelium during sepsis. Targeting this interaction may offer a new therapeutic strategy for septic ALI.
2026-06-30 | GSE336039 | GEO
Project description:Ubiquitylation plays an important role in the control of Na+ homeostasis by the kidney. It is well established that the epithelial Na+ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney, and is also a circadian output gene. In heterologous expression systems USP2-45 binds to ENaC, deubiquitylates it and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na+ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that the USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences to wild-type littermates with respect to the diurnal control of Na+ or K+ urinary excretion and plasma levels neither on standard diet, nor after acute and chronic changes to low and high Na+ diets, respectively. Moreover, they had similar aldosterone levels either at low or high Na+ diet. Blood pressure measurements using telemetry did not reveal variations as compared to control mice. Usp2-KO did neither display alternations in ENaC or Na+,Cl--cotransporter (NCC) expression, nor were there any changes in regulatory protein levels, as evidenced by immunoblotting and transcriptome analysis. We conclude that USP2-45 is not crucial for the regulation of Na+ balance or maintenance of blood pressure in vivo.
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Project description:Ubiquitylation plays an important role in the control of Na+ homeostasis by the kidney. It is well established that the epithelial Na+ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney, and is also a circadian output gene. In heterologous expression systems USP2-45 binds to ENaC, deubiquitylates it and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na+ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that the USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences to wild-type littermates with respect to the diurnal control of Na+ or K+ urinary excretion and plasma levels neither on standard diet, nor after acute and chronic changes to low and high Na+ diets, respectively. Moreover, they had similar aldosterone levels either at low or high Na+ diet. Blood pressure measurements using telemetry did not reveal variations as compared to control mice. Usp2-KO did neither display alternations in ENaC or Na+,Cl--cotransporter (NCC) expression, nor were there any changes in regulatory protein levels, as evidenced by immunoblotting and transcriptome analysis. We conclude that USP2-45 is not crucial for the regulation of Na+ balance or maintenance of blood pressure in vivo. We compared gene expression in kidneys from Usp2 Knock-Out versus Wild-Type. Six pairs of male littermates Usp2-KO and WT were combined in two pools per condition (3 animals per pool) keeping the littermate pairing between pools.
2013-01-16 | E-GEOD-43517 | biostudies-arrayexpress
Project description:Renal transcriptome analysis of Usp2 knockout mice. Please note 'Zeitgeber time 12' means 12 hours after light onset in 12h: light 12h dark housing conditions. It is of importance in the present design because of the strong circadian oscillation of the interest gene. In the Characteristics[genetic modification] column Usp2-Lac0-SA-IRES-lacZ-WT Neo/Kan is the name of the targeting cassette which was inserted in the gene, in opposition to non for the WT who carry no mutation.
2013-03-20 | E-MTAB-1442 | biostudies-arrayexpress
Project description:In prostate cancer, the development of resistance to androgen receptor (AR)-targeted therapies (ATTs) and chemotherapies is associated with the emergence of new phenotypic states with altered molecular features. Here, we identify ubiquitin-specific peptidase 2 (USP2) as a mediator of this phenomenon. USP2 is induced in response to ATTs and more highly expressed in aggressive, castration-resistant prostate tumours that have lost dependence on AR as an oncogenic driver. Over-expression of USP2 in prostate cancer cells elicited elevated rates of glycolysis, neuroendocrine features and resistance to docetaxel, a taxane chemotherapeutic that is a mainstay treatment for advanced prostate cancer. USP2 stabilises key oncoproteins including Aurora kinase A, cyclin D1 and fatty acid synthase. An unbiased proteomic approach identified potential new USP2 substrates and a USP2-regulated proteome that is associated with metastatic disease. Genetic or pharmacological targeting of USP2 caused cell death in human and mouse models of aggressive prostate cancer, and the USP2 inhibitor ML364 exhibited potent anti-tumour effects against an orthotopic xenograft model of AR-null disease. Collectively, this study identifies USP2 as a key regulator of proteins involved in prostate cancer progression and therapy resistance, positioning it as a viable therapeutic target.
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Project description:The homologous Ace2 and Swi5 transcription factors of Saccharomyces cerevisiae have identical DNA-binding domains, and both are cell cycle regulated. There are common target genes, as well as genes activated only by Ace2 and other genes activated only by Swi5. Keywords: genetic modification RNA was isolated from four strains: wild type, ace2 gene deletion, swi5 gene deletion, and the ace2 swi5 double gene deletion. RNAs from the three mutant strains were compared to wild type RNA in a microarray hybridization experiment.
2008-05-13 | E-GEOD-11380 | biostudies-arrayexpress
Project description:So far, we have found PMA induced USP2b isoform in myeloid leukemia cell lines such as HL60, THP-1, and U937. To explore molecular function of USP2 in the cells, we assess expression profiles of HL60-derivatives continuously expressing shRNA for USP2 and control shRNA.
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