USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes
USP25 Ameliorates Pathological Cardiac Hypertrophy by Stabilizing SERCA2a in Cardiomyocytes
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USP25 通过稳定心肌细胞中的 SERCA2a 改善病理性心脏肥大
DOI：
10.1161/circresaha.122.321849
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发表时间：
2023-02
影响因子：
20.1
通讯作者：
Guang Liang
中科院分区：
文献类型：
--
作者：
Bozhi Ye;Hao Zhou;Yanghao Chen;Wu Luo;Wante Lin;Ying Zhao;Jibo Han;Xue Han;Weijian Huang;Gaojun Wu;Xu Wang;Guang Liang
背景：病理性心脏肥大可导致心力衰竭，是全球死亡的主要原因之一。了解病理性心肌肥厚的分子机制将有助于心力衰竭的治疗。DUBs（去泛素化酶）通过精确控制蛋白质功能、定位和降解对心脏病理生理学至关重要。本研究旨在探讨泛素特异性肽酶25（ubiquitin-specific peptidase 25，USP 25）在病理性心肌肥厚中的作用及其分子机制。研究方法：在响应于Ang II（血管紧张素II）和横向主动脉缩窄刺激的鼠心肌细胞中以及在心力衰竭患者的肥大心肌组织中评价USP 25在心肌肥大中的作用。液相色谱质谱/质谱分析结合Co-IP用于鉴定SERCA 2a（肌质/内质网Ca 2 +-ATP酶2A），一种抗肥大蛋白，作为USP 25的相互作用蛋白。为了阐明USP 25调节SERCA 2a的分子机制，我们构建了一系列USP 25突变体质粒。此外，我们用腺相关病毒血清型9载体在心脏中过表达USP 25和SERCA 2a，以验证USP 25和SERCA 2a相互作用的生物学功能。结果如下：我们发现增加的蛋白水平的USP 25在小鼠心肌细胞血管紧张素II和横向主动脉缩窄刺激和肥厚的心肌组织的心力衰竭患者。USP 25缺乏加重了Ang II和横主动脉缩窄治疗下的心脏肥大和心功能不全。从机制上讲，USP 25通过其USP（泛素特异性蛋白酶）结构域和USP 25第178位的半胱氨酸直接与SERCA 2a结合，通过去除K48泛素链和防止蛋白酶体途径降解来发挥去泛素化作用以维持SERCA 2a蛋白的稳定性，从而维持心肌细胞中的钙处理。此外，在USP 25 −/−小鼠中通过腺相关病毒血清型9载体恢复USP 25表达可减轻Ang II诱导的心脏肥大和心功能不全，而心肌过表达SERCA 2a可模拟USP 25的作用。结论：我们证实USP 25通过去泛素化和稳定SERCA 2a抑制心肌肥厚。
Background: Pathological cardiac hypertrophy can lead to heart failure and is one of the leading causes of death globally. Understanding the molecular mechanism of pathological cardiac hypertrophy will contribute to the treatment of heart failure. DUBs (deubiquitinating enzymes) are essential to cardiac pathophysiology by precisely controlling protein function, localization, and degradation. This study set out to investigate the role and molecular mechanism of a DUB, USP25 (ubiquitin-specific peptidase 25), in pathological cardiac hypertrophy. Methods: The role of USP25 in myocardial hypertrophy was evaluated in murine cardiomyocytes in response to Ang II (angiotensin II) and transverse aortic constriction stimulation and in hypertrophic myocardium tissues of heart failure patients. Liquid chromotography with mass spectrometry/mass spectrometry analysis combined with Co-IP was used to identify SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2A), an antihypertrophy protein, as an interacting protein of USP25. To clarify the molecular mechanism of USP25 in the regulation of SERCA2a, we constructed a series of mutant plasmids of USP25. In addition, we overexpressed USP25 and SERCA2a in the heart with adenoassociated virus serotype 9 vectors to validate the biological function of USP25 and SERCA2a interaction. Results: We revealed increased protein level of USP25 in murine cardiomyocytes subject to Ang II and transverse aortic constriction stimulation and in hypertrophic myocardium tissues of patients with heart failure. USP25 deficiency aggravated cardiac hypertrophy and cardiac dysfunction under Ang II and transverse aortic constriction treatment. Mechanistically, USP25 bound to SERCA2a directly via its USP (ubiquitin-specific protease) domain and cysteine at position 178 of USP25 exerts deubiquitination to maintain the stability of the SERCA2a protein by removing the K48 ubiquitin chain and preventing proteasomal pathway degradation, thereby maintaining calcium handling in cardiomyocytes. Moreover, restoration of USP25 expression via adenoassociated virus serotype 9 vectors in USP25−/− mice attenuated Ang II-induced cardiac hypertrophy and cardiac dysfunction, whereas myocardial overexpression of SERCA2a could mimic the effect of USP25. Conclusions: We confirmed that USP25 inhibited cardiac hypertrophy by deubiquitinating and stabilizing SERCA2a.
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影响因子：
64.8
作者：
Kho, Changwon;Lee, Ahyoung;Jeong, Dongtak;Oh, Jae Gyun;Chaanine, Antoine H.;Kizana, Eddy;Park, Woo Jin;Hajjar, Roger J.
通讯作者：
Hajjar, Roger J.
DOI：
10.1038/s41569-020-00480-6
发表时间：
2021-06
期刊：
Nature reviews. Cardiology
影响因子：
--
作者：
Mishra S;Kass DA
通讯作者：
Kass DA
MicroRNA-200c 靶向的 contactin 1 通过加速 MAVS 的降解来促进甲型流感病毒的复制。
影响因子：
6.7
作者：
Xu S;Han L;Wei Y;Zhang B;Wang Q;Liu J;Liu M;Chen Z;Wang Z;Chen H;Zhu Q
通讯作者：
Zhu Q
DOI：
10.1016/j.jcmgh.2022.07.013
发表时间：
2022
影响因子：
7.2
作者：
Liu, Xin;Luo, Wu;Chen, Jiahao;Hu, Chenghong;Mutsinze, Rumbidzai N;Wang, Xu;Zhang, Yanmei;Huang, Lijiang;Zuo, Wei;Liang, Guang;Wang, Yi
通讯作者：
Wang, Yi
影响因子：
4.6
作者：
Kawaguchi K;Uo K;Tanaka T;Komada M
通讯作者：
Komada M