Fielitz Jens, van Rooij Eva, Spencer Jeffrey A, Shelton John M, Latif Shuaib, van der Nagel Roel, Bezprozvannaya Svetlana, de Windt Leon, Richardson James A, Bassel-Duby Rhonda, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4377-82. doi: 10.1073/pnas.0611726104. Epub 2007 Mar 2.
RING-finger proteins commonly function as ubiquitin ligases that mediate protein degradation by the ubiquitin-proteasome pathway. Muscle-specific RING-finger (MuRF) proteins are striated muscle-restricted components of the sarcomere that are thought to possess ubiquitin ligase activity. We show that mice lacking MuRF3 display normal cardiac function but are prone to cardiac rupture after acute myocardial infarction. Cardiac rupture is preceded by left ventricular dilation and a severe decrease in cardiac contractility accompanied by myocyte degeneration. Yeast two-hybrid assays revealed four-and-a-half LIM domain (FHL2) and gamma-filamin proteins as MuRF3 interaction partners, and biochemical analyses showed these proteins to be targets for degradation by MuRF3. Accordingly, FHL2 and gamma-filamin accumulated to abnormal levels in the hearts of mice lacking MuRF3. These findings reveal an important role of MuRF3 in maintaining cardiac integrity and function after acute myocardial infarction and suggest that turnover of FHL2 and gamma-filamin contributes to this cardioprotective function of MuRF3.
泛素连接酶通常作为泛素连接酶发挥作用，通过泛素-蛋白酶体途径介导蛋白质降解。肌肉特异性泛素连接酶（MuRF）蛋白是肌节中横纹肌限制性成分，被认为具有泛素连接酶活性。我们发现，缺乏MuRF3的小鼠心脏功能正常，但在急性心肌梗死后易发生心脏破裂。心脏破裂之前会出现左心室扩张和心脏收缩力严重下降，并伴有心肌细胞变性。酵母双杂交试验显示，四又二分之一LIM结构域（FHL2）和γ-肌动蛋白是MuRF3的相互作用伙伴，生化分析表明这些蛋白是MuRF3降解的靶标。因此，FHL2和γ-肌动蛋白在缺乏MuRF3的小鼠心脏中积累到异常水平。这些发现揭示了MuRF3在急性心肌梗死后维持心脏完整性和功能方面的重要作用，并表明FHL2和γ-肌动蛋白的周转有助于MuRF3的这种心脏保护功能。
