The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor
The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor
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去泛素酶 UCHL1 通过稳定表皮生长因子受体调节心脏肥大
DOI：
10.1126/sciadv.aax4826
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Li, Hui-Hua
中科院分区：
文献类型：
--
作者：
Bi, Hai-Lian;Zhang, Xiao-Li;Li, Hui-Hua
UCHL 1通过稳定EGFR积极调节心脏肥大，并将其作为一个未知的治疗靶点。病理性心脏肥大导致心力衰竭（HF）。泛素-蛋白酶体系统（UPS）在维持蛋白质稳态和心脏功能方面起着关键作用。然而，去泛素化酶（DUBs）在心脏功能中的作用的研究是有限的。在这里，我们观察到去泛素化酶泛素C-末端水解酶1（UCHL 1）显着上调激动剂刺激的原代心肌细胞和肥厚和衰竭的心脏。在心肌细胞和小鼠心脏中敲低UCHL 1显著改善激动剂或压力超负荷诱导的心脏肥大。相反，UCHL 1的过表达在心肌细胞和rAAV 9-UCHL 1处理的小鼠中具有相反的效果。机制上，UCHL 1结合，去泛素化，并稳定表皮生长因子受体（EGFR）和激活其下游介质。全身给予UCHL 1抑制剂LDN-57444可显著逆转心脏肥大和重塑。这些发现表明UCHL 1通过稳定EGFR积极调节心肌肥厚，并将UCHL 1确定为肥厚治疗的靶点。
UCHL1 positively regulates cardiac hypertrophy via stabilizing EGFR and highlighting it as a yet unknown therapeutic target. Pathological cardiac hypertrophy leads to heart failure (HF). The ubiquitin-proteasome system (UPS) plays a key role in maintaining protein homeostasis and cardiac function. However, research on the role of deubiquitinating enzymes (DUBs) in cardiac function is limited. Here, we observed that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) was significantly up-regulated in agonist-stimulated primary cardiomyocytes and in hypertrophic and failing hearts. Knockdown of UCHL1 in cardiomyocytes and mouse hearts significantly ameliorated cardiac hypertrophy induced by agonist or pressure overload. Conversely, overexpression of UCHL1 had the opposite effect in cardiomyocytes and rAAV9-UCHL1–treated mice. Mechanistically, UCHL1 bound, deubiquitinated, and stabilized epidermal growth factor receptor (EGFR) and activated its downstream mediators. Systemic administration of the UCHL1 inhibitor LDN-57444 significantly reversed cardiac hypertrophy and remodeling. These findings suggest that UCHL1 positively regulates cardiac hypertrophy by stabilizing EGFR and identify UCHL1 as a target for hypertrophic therapy.