Cardiomyocyte USP20 alleviates septic cardiomyopathy by deubiquitinating and inhibiting NLRP3 activity

IF 6.8 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Shanshan Dai, Yucong Zhang, Ziyi Huang, Yunxuan Chen, Zexin Yang, Ruihan Zheng, Keke Ye, Lingfeng Zhong, Xiangtao Zheng, Xueli Cai, Weijian Huang
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引用次数: 0

Abstract

Objectives

Although extensive research on septic cardiomyopathy has been conducted, effective therapies are still limited. Ubiquitin-specific peptidase 20 (USP20), a deubiquitinating enzyme, is critical in regulating protein ubiquitination and various cellular processes. whether USP20 is involved in the pathogenesis of septic cardiomyopathy remains unclear. This study investigated the impact of USP20 on septic cardiomyopathy.

Methods

The cardiomyocyte-specific USP20 knockout mice (USP20CKO) and NLRP3 knockout mice (NLRP3-/-) were used in the present study. A sepsis mouse model was established using lipopolysaccharide (LPS) administration and the cecal ligation and puncture (CLP) procedure. Recombinant adeno-associated virus serotype 9 (AAV9) was used to achieve overexpression of USP20. Myocardial function, histopathological changes, and pyroptosis levels in heart tissues were evaluated. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and co-immunoprecipitation (co-IP) were performed to identify the molecular mechanism of USP20 in septic cardiomyopathy.

Results

Our results showed that USP20 was downregulated in the myocardium of septic mice. Cardiomyocyte-specific USP20 deficiency worsened myocardial injury and cardiac dysfunction induced by LPS and CLP. LC-MS/MS analysis and co-IP revealed NLRP3 as a substrate protein of USP20. Mechanistically, USP20 removed K63-linked ubiquitin from K243 via its active site C154, inhibiting NLRP3's interaction with ASC and suppressing its activation and subsequent pyroptosis. Moreover, overexpressing USP20 in cardiomyocytes reduced LPS-induced myocardial injury. Additionally, the protective effect of USP20 against LPS-induced damage was nullified in the absence of NLRP3 in mice.

Conclusions

These findings suggest that cardiomyocyte-derived USP20 is crucial in septic cardiomyopathy progression and may serve as a novel therapeutic target for managing septic cardiomyopathy.

Key points

  • Cardiomyocyte-derived USP20 is crucial in septic cardiomyopathy progression.
  • NLRP3 is identified as a substrate protein of USP20.
  • USP20 deubiquitinates NLRP3 by removing K63-linked ubiquitin at K243 residue via its active site C154, disrupting the interaction between NLRP3 and ASC, suppressing NLRP3 activation and subsequent pyroptosis.
  • USP20 may serve as a novel therapeutic target for managing septic cardiomyopathy

Abstract Image

心肌细胞USP20通过去泛素化和抑制NLRP3活性减轻脓毒性心肌病。
目的:尽管对脓毒性心肌病进行了广泛的研究,但有效的治疗方法仍然有限。泛素特异性肽酶20 (USP20)是一种去泛素化酶,在调节蛋白质泛素化和各种细胞过程中起重要作用。USP20是否参与脓毒性心肌病的发病机制尚不清楚。本研究探讨USP20对脓毒性心肌病的影响。方法:采用心肌细胞特异性USP20基因敲除小鼠(USP20CKO)和NLRP3基因敲除小鼠(NLRP3-/-)。采用脂多糖(LPS)给药和盲肠结扎穿刺(CLP)方法建立脓毒症小鼠模型。利用重组腺相关病毒血清型9 (AAV9)实现USP20的过表达。评估心肌功能、组织病理学改变和心脏组织焦亡水平。采用液相色谱串联质谱(LC-MS/MS)和免疫共沉淀法(co-IP)分析USP20在脓毒性心肌病中的分子机制。结果:脓毒症小鼠心肌中USP20表达下调。心肌细胞特异性USP20缺乏加重了LPS和CLP诱导的心肌损伤和心功能障碍。LC-MS/MS和co-IP分析显示NLRP3是USP20的底物蛋白。机制上,USP20通过K243的活性位点C154去除k63连接的泛素,抑制NLRP3与ASC的相互作用,抑制其活化和随后的焦亡。此外,心肌细胞中过表达USP20可减少lps诱导的心肌损伤。此外,在缺乏NLRP3的小鼠中,USP20对lps诱导的损伤的保护作用无效。结论:这些研究结果表明,心肌细胞来源的USP20在脓毒性心肌病的进展中起着至关重要的作用,可能成为治疗脓毒性心肌病的新靶点。关键点:心肌细胞来源的USP20在脓毒性心肌病的进展中至关重要。NLRP3被鉴定为USP20的底物蛋白。USP20通过其活性位点C154去除K243残基上k63连接的泛素,从而使NLRP3去泛素化,破坏NLRP3与ASC之间的相互作用,抑制NLRP3的活化和随后的焦亡。USP20可能作为治疗感染性心肌病的新靶点。
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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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