The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.

IF 13 1区 生物学 Q1 CELL BIOLOGY
Shuolin Liu, Yaguang Bi, Tianting Han, Yiran E Li, Qihang Wang, Ne Natalie Wu, Chenguo Xu, Junbo Ge, Ronggui Hu, Yingmei Zhang
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Abstract

Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.

Abstract Image

E3泛素连接酶MARCH2通过负调控PGAM5/MAVS/NLRP3轴抑制热蛋白沉积,从而保护心肌免受缺血再灌注损伤。
众所周知,炎症小体激活和细胞热解死亡是心血管疾病(如心肌缺血再灌注(I/R)损伤)的发病机制之一,但其潜在的调控机制仍不甚明了。我们在此报告了 E3 泛素连接酶膜相关 RING 手指蛋白 2(MARCH2)在缺血的人类心脏或小鼠心脏受到 I/R 损伤时的表达水平升高。基因消融 MARCH2 会加重心肌梗死和心肌 I/R 损伤时的心功能障碍。单细胞RNA-seq分析表明,MARCH2的缺失会促使心肌细胞中的NLRP3炎性体活化。从机理上讲,研究发现磷酸甘油酸突变酶5(PGAM5)是MAVS-NLRP3信号转导的新型调控因子,它能与MAVS形成液-液相分离凝结物,促进NLRP3的招募。MARCH2 直接与 PGAM5 相互作用,促进其与 K48 链接的多泛素化和蛋白酶体降解,从而减少 PGAM5-MAVS 的共同凝结,进而抑制 NLRP3 炎性体的激活和心肌细胞的脓毒症。以 AAV 为基础重新引入 MARCH2 能显著改善 I/R 诱导的小鼠心脏功能障碍。总之,我们的研究结果揭示了一种新的机制,即MARCH2介导的泛素化负向调节PGAM5/MAVS/NLRP3轴,从而保护心肌细胞免受脓毒症和心肌I/R损伤。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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