Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure.
Ufm1-Specific Ligase Ufl1 Regulates Endoplasmic Reticulum Homeostasis and Protects Against Heart Failure.
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DOI：
10.1161/circheartfailure.118.004917
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Su H
中科院分区：
文献类型：
--
作者：
Li J;Yue G;Ma W;Zhang A;Zou J;Cai Y;Tang X;Wang J;Liu J;Li H;Su H
蛋白质稳态的缺陷足以引起心脏重塑和功能障碍。虽然泛素和泛素样蛋白的翻译后修饰正在成为一个重要的蛋白质功能的调节机制，Ufm1，一种新的泛素样蛋白的作用，还没有被探索在正常或应激心脏。蛋白质印迹法显示，Ufm1特异性连接酶1（Ufl1），Ufm1修饰所必需的酶，在肥大小鼠心脏中增加，但在扩张型心肌病患者的衰竭心脏中减少。为了确定Ufl1在心脏中的功能作用，我们产生了心脏特异性敲除小鼠，并表明Ufl1缺陷小鼠发生了年龄依赖性心肌病和心力衰竭，如心脏胎儿基因表达升高，纤维化增加和心肌收缩力受损所示。与对照组相比，Ufl1缺陷心脏在压力超负荷下表现出明显更大的肥大、纤维化加剧和心肌收缩力恶化。转录组分析表明，与内质网（ER）功能相关的基因在Ufl1缺陷的心脏中失调。生化分析显示，过度的ER应激先于Ufl1缺陷心脏中心肌病的发展，并沿着恶化。从机制上讲，Ufl1耗竭损害PERK信号传导，加重ER应激后的心肌细胞死亡。给Ufl1缺陷小鼠施用化学雌激素受体伴侣牛磺熊去氧胆酸减轻了雌激素受体应激并减弱了压力超负荷引起的心功能障碍。我们的研究结果提出了一个新的概念，即Ufm1系统是必不可少的心脏稳态，通过调节ER功能和心肌Ufl1的上调可以保护心脏衰竭。
Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although post-translational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1, a novel ubiquitin-like protein, has not been explored in either the normal or stressed heart. Western blotting revealed that Ufm1 specific ligase 1 (Ufl1), an enzyme essential for Ufm1 modification, was increased in hypertrophic mouse hearts but reduced in the failing hearts of patients with dilated cardiomyopathy. To determine the functional role of Ufl1 in the heart, we generated a cardiac-specific knockout mouse and showed that Ufl1-deficient mice developed age-dependent cardiomyopathy and heart failure, as indicated by elevated cardiac fetal gene expression, increased fibrosis and impaired cardiac contractility. When challenged with pressure overload, Ufl1-deficient hearts exhibited remarkably greater hypertrophy, exacerbated fibrosis and worsened cardiac contractility compared with control counterparts. Transcriptome analysis identified that genes associated with the endoplasmic reticulum (ER) function were dysregulated in Ufl1-deficient hearts. Biochemical analysis revealed that excessive ER stress preceded and deteriorated along with the development of cardiomyopathy in Ufl1-deficient hearts. Mechanistically, Ufl1 depletion impaired PERK signaling and aggravated cardiomyocyte cell death following ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction. Our results advance a novel concept that the Ufm1 system is essential for cardiac homeostasis through regulation of ER function and that upregulation of myocardial Ufl1 could be protective against heart failure.