Background:Defects in protein homeostasis are sufficient to provoke cardiac remodeling and dysfunction. Although posttranslational modifications by ubiquitin and ubiquitin-like proteins are emerging as an important regulatory mechanism of protein function, the role of Ufm1 (ubiquitin-fold modifier 1)—a novel ubiquitin-like protein—has not been explored in either the normal or stressed heart.Methods and Results:Western blotting revealed that Ufl1 (Ufm1-specific E3 ligase 1)—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 (PKR-like ER-resident kinase) signaling and aggravated cardiomyocyte cell death after ER stress. Administration of the chemical ER chaperone tauroursodeoxycholic acid to Ufl1-deficient mice alleviated ER stress and attenuated pressure overload-induced cardiac dysfunction.Conclusions: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.

中文翻译：

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Ufm1特异性连接酶Ufl1调节内质网稳态并防止心力衰竭

背景：蛋白质稳态的缺陷足以引起心脏重塑和功能障碍。尽管泛素和类泛素蛋白的翻译后修饰已成为蛋白质功能的重要调节机制，但在正常或应激状态下都未研究过Ufm1（泛素折叠修饰子1）的作用（一种新型的泛素样蛋白）。方法与结果：Western印迹显示，肥大的小鼠心脏中Ufl1（Ufm1特异性E3连接酶1）（一种修饰Ufm1的必需酶）有所增加，而在衰竭的扩张型心肌病患者的心脏中有所减少。为了确定Ufl1在心脏中的功能，我们产生了一只心脏特异性的基因敲除小鼠，并显示Ufl1缺陷小鼠发展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，纤维化增加和心脏收缩力受损所表明的。当受到压力超负荷的挑战时，与对照组相比，缺乏Ufl1的心脏表现出明显更大的肥大，加剧的纤维化以及心脏收缩性的恶化。转录组分析发现在Ufl1缺乏的心脏中与内质网（ER）功能相关的基因失调。生化分析显示，在缺乏Ufl1的心脏中，过度的ER应激会随着心肌病的发展而发生并恶化。机械上，Ufl1耗竭受损（PKR样内质网驻留激酶）信号和内质网应激后心肌细胞死亡加剧。