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A K63-Ubiquitination Dependent Necroptosis Signaling Network in the Heart

心脏中 K63 泛素化依赖性坏死性凋亡信号网络

基本信息

批准号：
10090946
负责人：
Qinghang Liu
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-08 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10090946
关键词：
Ablation Acute Address Adult Apoptosis Attenuated Biological Cardiac Cardiac Myocytes Caspase Cell Death Signaling Process Cell membrane Cessation of life Complex Data Dilated Cardiomyopathy Disease Enzymes Gene Transfer Genetic Goals Heart Heart Injuries Heart failure Investigation Link MAP3K7 gene Mediating Mitochondria Modeling Molecular Mus Myocardial Myocardial Ischemia Necrosis Organelles Pathologic Pathway interactions Phosphorylation Physiology Pilot Projects Play Polyubiquitination Process RIPK1 gene RIPK3 gene Regulation Reperfusion Injury Role Signal Transduction Swelling TNF receptor-associated factor 2 TNFRSF1A gene TRAF2 gene Testing Therapeutic Ubiquitination cardioprotection experimental study gain of function in vivo insight ischemic injury myocardial injury novel overexpression prevent receptor therapeutic target ubiquitin ligase ubiquitin-protein ligase vector

项目摘要

Project Summary/Abstract Loss of cardiomyocytes by apoptosis and/or necrosis is a hallmark of cardiac ischemic injury, pathological remodeling, and end-stage heart failure. Although necrosis was traditionally regarded as a passive and unregulated process, emerging evidence has shifted this paradigm and identified several forms of “programmed necrosis”, including death receptor-mediated necrosis (termed “necroptosis”), mitochondria-mediated necrosis, and other regulated necrotic processes. Despite recent progress, how necroptosis is regulated in the heart remain largely unknown and preventing necroptotic cardiomyocyte death is still an important challenge. Our pilot studies identified a new K63-linked polyubiquitination (K63-Ub) dependent necroptosis signaling network that critically regulates cardiac ischemic injury and pathological remodeling. Intriguingly, the K63-deubiquitinase CYLD (cylindromatosis) was markedly up-regulated, whereas the E3 ubiquitin ligase TRAF2 (TNF receptor associated factor-2) was down-regulated, in the heart after ischemia-reperfusion injury. Our preliminary results further identified CYLD and TRAF2 as an activator and a suppressor of myocardial necroptosis, respectively. Importantly, cardiomyocyte-specific ablation of CYLD attenuated ischemic injury and adverse remodeling by inhibiting necroptosis. Acute deletion of TRAF2 in the adult heart caused dilated cardiomyopathy by promoting necroptosis, whereas TRAF2 gene transfer elicited cardioprotection. Mechanistically, we propose a new K63- Ub dependent necroptotic regulatory mechanism whereby CYLD deubiquitinates TRAF2 and TAK1, disrupts TAK1-RIP1 interaction, and promotes the necroptotic complex. As an opposing mechanism, TRAF2 acts as an E3 ligase for TAK1 to inhibit necroptosis signaling. Thus, the reversible K63-Ub (mainly non-proteolytic) constitutes a new paradigm of necroptosis signaling with important biological implications. We hypothesize that the deubiquitinase CYLD, in conjunction with the E3 ligase TRAF2, critically regulate myocardial necroptosis, ischemic injury, and remodeling, thus representing promising therapeutic targets. Aim 1 will investigate the opposing roles of K63-Ub modifying enzymes CYLD and TRAF2 in regulating myocardial necroptosis and ischemic injury in vivo. Aim 2 will define a CYLD/TRAF2 mediated, K63-Ub dependent necroptosis signaling network in cardiomyocytes. Using genetic and molecular strategies, we will investigate the opposing roles of CYLD and TRAF2 in regulating myocardial necroptosis under basal conditions and in the setting of ischemic injury. The proposed studies will provide new insights into the molecular regulation and functional significance of necroptosis in the heart, which has important translational implications, especially given our preliminary results revealing CYLD/TRAF2 as key necroptotic regulators and promising targets for ischemic heart disease.

项目总结/文摘