ArticleJournal of molecular and cellular cardiology2015
Cardiomyocyte-specific overexpression of the ubiquitin ligase Wwp1 contributes to reduction in Connexin 43 and arrhythmogenesis.
Article in Journal of molecular and cellular cardiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Bioinformatics Identification and Molecular Docking Validation of Post-Translational Modification-Related Hub Genes as Diagnostic Biomarkers and Therapeutic Targets in Myocardial Fibrosis.International journal of molecular sciences · 2026Article
- Identification and validation of an interaction between the E3 ubiquitin ligase WWP1 and the Transcriptional Co-Activator WBP2 in the human heart.Biology open · 2026Article
- Review
- Degradation of voltage-gated calcium channels: mechanisms and applications in neurological and cardiovascular diseases.Cell communication and signaling : CCS · 2025Review
- Review
- The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation.Cellular and molecular life sciences : CMLS · 2024Article
- Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.Molecular biology reports · 2024Review
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- The potential roles of stress-induced phosphoprotein 1 and connexin 43 in rats with reperfusion arrhythmia.Immunity, inflammation and disease · 2023Article
- Endocytosis and Endocytic Motifs across the Connexin Gene Family.International journal of molecular sciences · 2023Article
- Changes of ubiquitylated proteins in atrial fibrillation associated with heart valve disease: proteomics in human left atrial appendage tissue.Frontiers in cardiovascular medicine · 2023Article
- Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation.Theranostics · 2023Article
- Ubiquitin ligaseAmerican journal of physiology. Heart and circulatory physiology · 2021Article
- The Role of HECT-Type E3 Ligase in the Development of Cardiac Disease.International journal of molecular sciences · 2021Review
- Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease.International journal of molecular sciences · 2021Review
- WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity.Frontiers in cell and developmental biology · 2021Article
- Article
- The ubiquitin ligase WWP1 contributes to shifts in matrix proteolytic profiles and a myocardial aging phenotype with diastolic heart.American journal of physiology. Heart and circulatory physiology · 2020Article
- Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.American journal of medical genetics. Part A · 2020Article
- Regulation of gap junction intercellular communication by connexin ubiquitination: physiological and pathophysiological implications.Cellular and molecular life sciences : CMLS · 2020Review
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11 authors.
Funding
Abstract
Gap junctions (GJ) are intercellular channels composed of connexin subunits that play a critical role in a diverse number of cellular processes in all tissue types. In the heart, GJs mediate electrical coupling between cardiomyocytes and display mislocalization and/or downregulation in cardiac disease (a process known as GJ remodeling), producing an arrhythmogenic substrate. The main constituent of GJs in the ventricular myocardium is Connexin 43 (Cx43), an integral membrane protein that is rapidly turned over and shows decreased expression or function with age. We hypothesized that Wwp1, an ubiquitin ligase whose expression in known to increase in aging-related pathologies, may regulate Cx43 in vivo by targeting it for ubiquitylation and degradation and yield tissue-specific Cx43 loss of function phenotypes. When Wwp1 was globally overexpressed in mice under the control of a β-actin promoter, the highest induction of Wwp1 expression was observed in the heart which was associated with a 90% reduction in cardiac Cx43 protein levels, left ventricular hypertrophy (LVH), and the development of lethal ventricular arrhythmias around 8weeks of age. This phenotype was completely penetrant in two independent founder lines. Cardiomyocyte-specific overexpression of Wwp1 confirmed that this phenotype was cell autonomous and delineated Cx43-dependent and -independent roles for Wwp1 in arrhythmogenesis and LVH, respectively. Using a cell-based system, it was determined that Wwp1 co-immunoprecipitates with and ubiquitylates Cx43, causing a decrease in the steady state levels of Cx43 protein. These findings offer new mechanistic insights into the regulation of Cx43 which may be exploitable in various gap junctionopathies.
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