Wrestling stress: role of ufm1 modification in pathological cardiac remodeling

摔跤应激：ufm1 修饰在病理性心脏重塑中的作用

基本信息

批准号：
9887887
负责人：
Jie Li
金额：
$ 38.28万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887887
关键词：
Ablation Address Aging Animals Binding Binding Proteins Biochemical Biological Process Cardiac Cardiac Myocytes Cardiomyopathies Cell physiology Cessation of life Data Development Dilated Cardiomyopathy Dimerization Disease Embryo Embryonic Development Endoplasmic Reticulum Event Fibroblasts Foundations Functional disorder Genetic Polymorphism Genetically Engineered Mouse Goals Heart Heart Diseases Heart failure Hematopoiesis Homeostasis Hospitalization Human Intervention Knowledge Lead Ligase Mediating Modeling Modification Molecular Molecular Target Mus Myocardial dysfunction Neurons Pathogenesis Pathogenicity Pathologic Pharmacology Physiological Pilot Projects Post-Translational Protein Processing Proteins Publishing RNA Splicing Regulation Reporting Research Rest Role Signal Transduction Stress Stress Response Signaling Testing Time Transducers Treatment Efficacy Ubiquitin Ubiquitin Like Proteins Ubiquitination Wrestling attenuation base biological adaptation to stress cardioprotection cell injury clinical practice combat endoplasmic reticulum stress heart function hemodynamics human disease in vivo intestinal homeostasis loss of function mutation novel pressure prevent response restoration tool transcriptomics

项目摘要

PROJECT SUMMARY Protein post-translational modifications by ubiquitin and ubiquitin-like proteins represent vital mechanisms regulating protein quality and function that are integral to cardiomyocyte function and homeostasis. The overall goal of this proposal is to determine the function and underlying mechanism of a novel ubiquitin-like protein, Ubiquitin-fold modifier 1 (Ufm1), in the heart. Ufmylation covalently conjugates Ufm1 to target substrates via a Ufm1-specific E1 (Uba5)-E2 (Ufc1)-E3 (Ufl1) cascade. Through regulating the function of cellular proteins, ufmylation controls multiple cellular processes and physiological events, and have been implicated in a number of human diseases. Our pilot studies have for the first time identified a critical role for ufmylation in constraining pathological cardiac remodeling and provided novel mechanistic linkages between ufmylation and endoplasmic reticulum (ER) stress response. Ufmylation is dysregulated in cardiomyopathic hearts. Inhibition of ufmylation via targeted ablation of the E3 Ufm1 ligase 1 (Ufl1) in the heart caused cardiomyopathy during ageing and promoted propensity to heart failure in response to hemodynamic stress. ER stress coincided with the progression of cardiomyopathy in these mice, and pharmacological attenuation of ER stress ameliorated cardiac dysfunction following pressure overload in Ufl1-deficient hearts. Furthermore, Ufl1 controls the expression of Ufm1 binding protein 1 (Ufbp1), an ER-resident Ufm1 target. Depletion of Ufbp1 diminished Xbp-1 splicing, blunted Xbp-1s signaling and aggravated ER stress-induced cell injury, recapitulating most aspects of Ufl1 depletion. Moreover, ER stress promotes the binding of Ufbp1 to IRE1α, a key ER stress transducer that activates cardioprotective Xbp-1s signaling. These data collectively suggest that Ufbp1 acts downstream of Ufl1 to protect CMs against pathogenic insults and is a crucial regulator of IRE1a/Xbp-1s signaling in cardiomyocytes. Therefore, this proposal is to test the hypothesis that ufmylation protects against pathological cardiac remodeling by targeting Ufbp1 to activate the adaptive ER stress response in cardiomyocytes. To test this hypothesis, Aim 1 will define the pathophysiological roles of Ufbp1 in the heart; Aim 2 will identify molecular bases of how ufmylation activates the adaptive ER stress response signaling in cardiomyocytes; Aim 3 will elucidate the functional importance of Ufbp1 ufmylation in activating IRE1a/Xbp-1s signaling and limiting cellular damage in response to stress. The proposed study is the first to target protein ufmylation in a model of cardiac failure and will employ unique tools including three new genetically-engineered mouse models to provide translational significance. Completion of this project will establish a novel role of post-translational modification (ufmylation) in the regulation of cardiac function and suggest new molecular targets for exploitation in the treatment of heart disease.

项目概要泛素和泛素样蛋白的蛋白质翻译后修饰代表重要机制调节心肌细胞功能和稳态不可或缺的蛋白质质量和功能。该提案的目标是确定一种新型泛素样蛋白的功能和潜在机制，心脏中的泛素折叠修饰剂 1 (Ufm1) 通过共价键将 Ufm1 与靶底物结合。 Ufm1特异性E1(Uba5)-E2(Ufc1)-E3(Ufl1)级联通过调节细胞蛋白的功能， ufmylation 控制多种细胞过程和生理事件，并与许多我们的试点研究首次确定了 ufmylation 在抑制人类疾病方面的关键作用。病理性心脏重塑并提供了 ufmylation 和内质之间的新机制联系心肌病心脏中网状 (ER) 应激反应失调。通过靶向消融心脏中的 E3 Ufm1 连接酶 1 (Ufl1)，导致衰老过程中的心肌病 ER应激反应与心力衰竭的倾向一致。这些小鼠心肌病的进展以及内质网应激的药理学减弱可改善心脏功能 Ufl1 缺陷心脏中压力超负荷后的功能障碍此外，Ufl1 控制着 Ufm1 结合蛋白 1 (Ufbp1)，一种 ER 驻留 Ufm1 靶标，Ufbp1 的耗尽会减少 Xbp-1 剪接， Xbp-1s 信号减弱和 ER 应激诱导的细胞损伤加剧，概括了 Ufl1 的大部分方面此外，内质网应激会促进 Ufbp1 与 IRE1α 的结合，IRE1α 是一种关键的内质网应激传感器。激活心脏保护性 Xbp-1s 信号传导这些数据共同表明 Ufbp1 在 Ufl1 下游发挥作用。保护 CM 免受致病性损伤，并且是心肌细胞中 IRE1a/Xbp-1s 信号传导的重要调节因子。因此，本提案旨在检验 ufmylation 可以预防病理性心脏重塑的假设为了验证这一假设，Aim 团队通过靶向 Ufbp1 来激活心肌细胞中的适应性 ER 应激反应。 1 将定义 Ufbp1 在心脏中的病理生理学作用；目标 2 将确定其作用的分子基础； ufmylation 激活心肌细胞中的适应性 ER 应激反应信号；目标 3 将阐明 Ufbp1 ufmylation 在激活 IRE1a/Xbp-1s 信号传导和限制细胞损伤中的功能重要性拟议的研究是第一个针对心力衰竭模型中的蛋白质乌酰化的研究。将采用独特的工具，包括三种新的基因工程小鼠模型来提供转化该项目的完成将确立翻译后修饰（ufmylation）的新作用。调节心脏功能并提出用于治疗心脏疾病的新分子靶标疾病。