Ask about this productRelated genes to: USP46 antibody
- Gene:
- USP46 NIH gene
- Name:
- ubiquitin specific peptidase 46
- Previous symbol:
- -
- Synonyms:
- FLJ12552
- Chromosome:
- 4q12
- Locus Type:
- gene with protein product
- Date approved:
- 2003-09-04
- Date modifiied:
- 2015-09-03
Related products to: USP46 antibody
Related articles to: USP46 antibody
- Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the Ubiquitin-Proteasome System (UPS), autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically regulate the degradation of critical synaptic components from AMPA and NMDA receptors to scaffolds like PSD-95 and SHANK3. We further explore how autophagy, including chaperone-mediated and activity-dependent forms, contributes to synaptic remodeling and quality control. Crucially, dysfunction of synaptic degradation pathways is a common thread in neurodevelopmental and neurodegenerative disorders. We summarize evidence linking proteostatic malfunction to the pathogenesis of Alzheimer's disease (through impaired clearance of Aβ and tau), Parkinson's disease (via α-synuclein turnover), epilepsy, autism spectrum disorder, and ischemic injury. The review highlights how genetic mutations in degradation machinery or their synaptic targets converge to disrupt synaptic integrity and neural circuit function. By integrating findings from basic neurobiology and disease models, this review underscores the central importance of synaptic proteostasis and aims to identify critical regulatory molecules that retain potentials for diagnostic biomarkers and therapeutic targets for neurological disease. - Source: PubMed
Publication date: 2026/04/29
Li YuanyuanHou Xiao-YuTao Yanmei - The ubiquitin-proteasome system (UPS) is important for podocyte health, but the specific UPS proteins involved in podocyte injury of diabetic nephropathy (DN) are not well known. Patients with DN have lower expression of USP46 in podocytes, which is linked to higher proteinuria. Deleting the Usp46 gene in podocytes of mice (Usp46 mice) led to spontaneous albuminuria and worsened podocyte injury and glomerular lesions under diabetic conditions. Mechanically, loss of USP46 caused cytosolic translocation and aggregation of TAR DNA binding protein 43 (TDP-43) in podocytes. Here, we identified acarbose as an agonist of USP46. Treatment with acarbose reduced TDP-43 aggregation in podocytes, prevented podocyte loss, and mitigated albuminuria in diabetic mice; the therapeutic efficacy of acarbose was abolished in Usp46 mice. This research elucidates the role of USP46 in podocyte homeostasis and injury in DN and indicates a potential therapeutic impact for acarbose in DN beyond the regulation of blood glucose concentrations through its activation of USP46. - Source: PubMed
Publication date: 2026/03/11
Hou QingHuang GuiqinKan ShuyanYang RuixiangMa ZijianZhu XiaodongZeng CaihongJiang SongLiu Zhihong - Ribosomal DNA copy number (rDNAcn) and DNA methylation are important modulators of the human genome, both studied in relation to overall cellular function, biological ageing, and disease development. Despite the overlapping roles, their relationship remains poorly understood, especially in the early stages of life, characterized by rapid growth and high cellular demands. Even though previous studies have associated rDNA methylation with cancer and ageing, no study to date has examined the interplay between rDNAcn and whole-genome DNA methylation. In an epigenome-wide association study of 45S rDNAcn variation in 194 newborns, we show strong positive associations between rDNAcn and single DNA methylated CpGs, measured with the Illumina EPIC array. Out of the 122 Bonferroni-significant CpGs, 63.5% were also Bonferroni-significant in a replication cohort of 167 newborns, in which a second EWAS was conducted using DNA methylation data from the Illumina 450K array. The identified CpGs were dispersed over the autosomes and were not functionally related to the rDNA-forming nucleolar-associated domains. The top CpGs were annotated to genes (, , , ) that are functionally linked to cancer and cellular proliferation. In downstream analyses, the 122 rDNAcn-related CpGs revealed 31 differentially methylated regions and 253 nominally significant correlations with cord blood gene transcripts in an eQTM analysis. Pathway enrichment analyses showed an overrepresentation of the following pathways: 'RNA Polymerase III transcription' (R-HSA-76071, R-HSA-76046, R-HSA-74158, R-HSA-749476, R-HSA-73780, R-HSA-73980, R-HSA-76066, R-HSA-76061, hsa03020), 'cytosolic sensors of pathogen-associated DNA' (R-HSA-1834949), 'RNA polymerase II transcribes snRNA genes' (R-HSA-6807505), and 'translation initiation' (R-HSA-72613, R-HSA-72737). Our findings reveal a close link between rDNAcn variation and DNA methylation in early life. Disruptions in this interplay may influence cellular functions critical for early development, potentially shaping health and disease trajectories later in life. - Source: PubMed
Publication date: 2026/03/03
Barth KathrinAlfano RossellaPlusquin MichelleWang CongrongNawrot Tim SMartens Dries S - The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic strategies. This study explores host-targeted therapies by focusing on deubiquitinating enzymes (DUBs), key regulators of the ubiquitin-proteasome system (UPS) that mediate host-pathogen interactions. Using -infected macrophages, we screened a UPS-targeted compound library and identified several compounds that enhanced bacterial clearance without affecting host cell viability. Among these, the dual USP25/USP28 inhibitor AZ-1 emerged as one of the top candidates. Transcriptomic profiling revealed infection-induced upregulation of DUBs, particularly USP25, USP46, and OTUD7B. USP25 knockdown significantly reduced intracellular , confirming its role as a critical host factor. AZ-1 also exhibited broad-spectrum intracellular activity against multidrug-resistant , , and . , AZ-1 reduced fecal bacterial loads, clinical scores, and infection-induced weight loss, though it did not extend survival. AZ-1 had no direct antibacterial activity in axenic culture, indicating a host-targeting mechanism. Transcriptomic and signaling analyses revealed AZ-1 suppressed key immune pathways, including nuclear factor-kappa B (NF-κB) signaling. These findings establish DUBs as promising targets for host-directed therapies and support further development of UPS-targeted agents to combat antimicrobial resistance.IMPORTANCEAntibiotic-resistant infections, particularly those caused by intracellular pathogens, represent an urgent public health threat due to their ability to evade immune responses and resist conventional antibiotics. This study identifies the ubiquitin-proteasome system, specifically deubiquitinating enzymes, as viable targets for host-directed therapy. We demonstrate that the USP25/USP28 inhibitor AZ-1 enhances intracellular bacterial clearance without compromising host cell viability and is effective against several multidrug-resistant gram-negative pathogens. Knockdown of USP25 alone also reduced intracellular , stressing out its proposed role in bacterial persistence. AZ-1 improved early infection outcomes but was insufficient as monotherapy. These findings support a novel therapeutic approach that targets host pathways to enhance bacterial clearance, offering a promising adjunct to traditional antibiotics in the fight against antimicrobial resistance. - Source: PubMed
Publication date: 2025/09/03
Santelices JohnSchultz AlexanderWalker AlyssaAdams NicoleTirado DeyaneiraBarker HaileyEshraghi AriaCzyż Daniel MFerraro Mariola J - Ankyrin2 (ANK2) has been found to be abnormally overexpressed in myocardial infarction (MI) cell models, but its role and related mechanisms in MI progression have not been explored. Cardiomyocytes (AC16) were subjected to hypoxia/reoxygenation (H/R) treatment to mimic MI cell models, and ischemia/reperfusion (I/R)-induced myocardial injury was used to establish MI rat models. Cell viability, apoptosis and mitochondrial membrane potential (MMP) depolarization were analyzed by CCK8 assay, flow cytometry and JC-1 staining. The levels of inflammatory-related factors and ferroptosis-related markers were determined by commercial kits. ANK2 and ubiquitin-specific peptidase 46 (USP46) protein levels were analyzed using western blot. Cycloheximide treatment assay and ubiquitination assay were used to confirm the regulation of USP46 on ANK2 protein stability and ubiquitination level. After H/R treatment, AC16 cell viability was reduced, while apoptosis, inflammation and ferroptosis were enhanced. ANK2 was upregulated in H/R-induced AC16 cells, and its knockdown repressed H/R-induced cardiomyocyte apoptosis, inflammation and ferroptosis. USP46 enhanced ANK2 protein stability and expression by deubiquitination. Overexpression of ANK2 also reversed the inhibition effect of USP46 knockdown on H/R-induced cardiomyocyte injury. In addition, downregulation of USP46 alleviated myocardial injury in I/R-induced rat models by decreasing ANK2 expression. USP46-stabilized ANK2 promoted cardiomyocyte apoptosis, inflammation and ferroptosis to aggravate MI process. - Source: PubMed
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