title: Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination.
abstract: Abro1 (also known as KIAA0157) is a scaffold protein that recruits polypeptides to assemble the BRISC (BRCC36-containing isopeptidase complex) deubiquitinating (DUB) enzyme. The four subunits of BRISC enzyme include Abro1, NBA1, BRE, and BRCC36 proteins. The DUB activity of the BRISC enzyme is exclusively directed against Lys63-linked polyubiquitin that does not have a proteolytic role but regulates protein function. In this report, we identified Abro1 as a specific interactor of THAP5, a zinc finger transcription factor that is involved in G2/M control and apoptosis. Abro1 was predominantly expressed in the heart and its protein level was regulated following experimentally induced myocardial ischemia/reperfusion (MI/R) injury. Furthermore, in patients with coronary artery disease (CAD), there was a dramatic increase in Abro1 protein level in the myocardial infarction (MI) area. Increase in Abro1 leads to a significant reduction in Lys63-linked ubiquitination of specific protein targets. Reducing the Abro1 protein level exacerbated cellular damage and cell death of cardiomyocytes due to MI/R injury. Additionally, overexpression of Abro1 in a heterologous system provided significant protection against oxidative stress-induced apoptosis. In conclusion, our results demonstrate that Abro1 protein level substantially increases in myocardial injury and coronary artery disease and this up-regulation is part of a novel cardioprotective mechanism. In addition, our data suggest a potential new link between Lys63-specific ubiquitination, its modulation by the BRISC DUB enzyme, and the development and progression of heart disease.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 12722 Research Parkway Orlando, FL 32826, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cilenti
authors.forename: Meenakshi P
authors.initials: MP
authors.lastname: Balakrishnan
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.forename: Camilla
authors.initials: C
authors.lastname: Ambivero
authors.forename: Martin
authors.initials: M
authors.lastname: Sterlicchi
authors.forename: Federica
authors.initials: F
authors.lastname: del Monte
authors.forename: Xin L
authors.initials: XL
authors.lastname: Ma
authors.forename: Antonis S
authors.initials: AS
authors.lastname: Zervos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D020798:Two-Hybrid System Techniques
chemical_list: D004268:DNA-Binding Proteins; D034521:Nuclear Matrix-Associated Proteins; D009687:Nuclear Proteins; C543178:THAP5 protein, human; D006861:Hydrogen Peroxide