Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)
Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)
复制标题
泛素c端水解酶L1 （UCHL1）通过糖调节蛋白78 kDa （GRP78）调控心肌梗死后心肌纤维化
DOI：
10.1038/s41598-020-67746-4
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发表时间：
2020-06-30
影响因子：
4.6
通讯作者：
Wang, Yanggan
中科院分区：
文献类型：
--
作者：
Lei, Qian;Yi, Tao;Wang, Yanggan
心肌纤维化异常提示心肌梗死患者心功能不全和预后不良。许多研究表明，泛素蛋白酶体系统（UPS）在纤维化的发病机制中起着重要作用。泛素C末端水解酶L1（UCHL 1）是UPS的成员，与多种心脏疾病的纤维化有关。然而，UCHL 1是否调节MI后的心脏纤维化尚未确定。在本研究中，我们发现UCHL 1在梗死心脏和TGF-β 1刺激的心脏成纤维细胞（CF）中显著增加。用LDN 57444（LDN）抑制UCHL 1逆转MI后心脏的心肌纤维化并改善心功能。LDN或UCHL 1 siRNA治疗可消除TGF-β 1诱导的CF纤维化反应。通过免疫沉淀-质谱联用技术进一步鉴定GRP 78为UCHL 1的相互作用因子。我们确定UCHL 1与葡萄糖调节蛋白78 kDa（GRP 78）相互作用，并通过泛素化促进GRP 78降解。此外，我们发现GRP 78在UCHL 1敲低后上调，GRP 78抑制剂HA 15减弱了TGF-β 1刺激的CF中UCHL 1敲低所发挥的抗纤维化功能。这表明UCHL 1通过与GRP 78相互作用调节MI后心脏纤维化。这项工作确定UCHL 1-GRP 78轴参与MI后的心脏纤维化。
Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-beta 1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-beta 1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitation-mass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-beta 1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI.