Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination.
Regulation of Abro1/KIAA0157 during myocardial infarction and cell death reveals a novel cardioprotective mechanism for Lys63-specific deubiquitination.
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DOI：
10.1016/j.yjmcc.2010.12.015
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发表时间：
2011-04
影响因子：
5
通讯作者：
Zervos AS
中科院分区：
文献类型：
--
作者：
Cilenti L;Balakrishnan MP;Wang XL;Ambivero C;Sterlicchi M;del Monte F;Ma XL;Zervos AS
Abro1(也称为KIAA0157)是一种支架蛋白，它招募多肽来组装BRISC(包含BRCC36的异肽酶复合体)去泛素酶(DUB)。BRISC酶的四个亚基包括Abro1、NBA1、Bre和BRCC36蛋白。BRISC酶的DUB活性是专门针对Lys63连接的多泛素的，该多泛素不起蛋白分解作用，但调节蛋白质功能。在这篇报道中，我们发现ABRO1是THAP5的特异性相互作用因子，THAP5是一种锌指转录因子，参与G2/M调控和细胞凋亡。在实验性心肌缺血/再灌注损伤后，Abro1主要在心脏表达，其蛋白水平受到调节。此外，在冠心病(CAD)患者中，心肌梗死(MI)区域的Abro1蛋白水平显著增加。Abro1的增加导致Lys63连接的特定蛋白质靶标的泛素化显著减少。降低Abro1蛋白水平加剧了心肌细胞的损伤和细胞死亡。此外，在异源系统中过表达Abro1对氧化应激诱导的细胞凋亡具有显著的保护作用。总之，我们的结果表明，在心肌损伤和冠状动脉疾病中，Abro1蛋白水平显著增加，这种上调是一种新的心脏保护机制的一部分。此外，我们的数据表明，Lys63特异性泛素化、BRISC Dub酶调节它与心脏病的发展和进展之间存在潜在的新联系。
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 lead 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.
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