School of Basic Medical Sciences, Shandong University, Ji'nan, Shandong 250012, PR China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
J Mol Cell Cardiol. 2020 Aug;145:59-73. doi: 10.1016/j.yjmcc.2020.06.004. Epub 2020 Jun 14.
Deubiquitinating enzymes (DUBs) appear to be a new class of regulators of cardiac homeostasis and disease. However, DUB-mediated signaling in the heart is not well understood. Herein we report a novel mechanism by which cylindromatosis (CYLD), a DUB mediates cardiac pathological remodeling and dysfunction. Cardiomyocyte-restricted (CR) overexpression of CYLD (CR-CYLD) did not cause gross health issues and hardly affected cardiac function up to age of one year in both female and male mice at physiological conditions. However, CR-CYLD overexpression exacerbated pressure overload (PO)-induced cardiac dysfunction associated with suppressed cardiac hypertrophy and increased myocardial apoptosis in mice independent of the gender. At the molecular level, CR-CYLD overexpression enhanced PO-induced increases in poly-ubiquitinated proteins marked by lysine (K)48-linked ubiquitin chains and autophagic vacuoles containing undegraded contents while suppressing autophagic flux. Augmentation of cardiac autophagy via CR-ATG7 overexpression protected against PO-induced cardiac pathological remodeling and dysfunction in both female and male mice. Intriguingly, CR-CYLD overexpression switched the CR-ATG7 overexpression-dependent cardiac protection into myocardial damage and dysfunction associated with increased accumulation of autophagic vacuoles containing undegraded contents in the heart. Genetic manipulation of Cyld in combination with pharmacological modulation of autophagic functional status revealed that CYLD suppressed autolysosomal degradation and promoted cell death in cardiomyocytes. In addition, Cyld gene gain- and/or loss-of-function approaches in vitro and in vivo demonstrated that CYLD mediated cardiomyocyte death associated with impaired reactivation of mechanistic target of rapamycin complex 1 (mTORC1) and upregulated Ras genes from rat brain 7 (Rab7), two key components for autolysosomal degradation. These results demonstrate that CYLD serves as a novel mediator of cardiac pathological remodeling and dysfunction by suppressing autolysosome efflux in cardiomyocytes. Mechanistically, it is most likely that CYLD suppresses autolysosome efflux via impairing mTORC1 reactivation and interrupting Rab7 release from autolysosomes in cardiomyocytes.
去泛素化酶（DUBs）似乎是心脏内稳态和疾病的一类新的调节因子。然而，DUB 介导的心脏信号通路尚未得到很好的理解。本文报道了一种新的机制，即去泛素化酶 CYLD 通过该机制介导心脏病理性重构和功能障碍。在生理条件下，心肌细胞特异性过表达 CYLD（CR-CYLD）在雌性和雄性小鼠中不会导致严重的健康问题，也不会对心脏功能产生显著影响，直到 1 岁。然而，CR-CYLD 的过表达加剧了压力超负荷（PO）引起的心脏功能障碍，与心脏肥大抑制和心肌细胞凋亡增加有关，而与性别无关。在分子水平上，CR-CYLD 的过表达增强了 PO 诱导的多泛素化蛋白增加，这些蛋白被赖氨酸（K）48 连接的泛素链标记，并含有未降解内容的自噬空泡。通过 CR-ATG7 的过表达增强心脏自噬，可防止 PO 诱导的雌性和雄性小鼠的心脏病理性重构和功能障碍。有趣的是，CR-CYLD 的过表达将 CR-ATG7 过表达依赖的心脏保护作用转化为心肌损伤和功能障碍，伴有心脏中含有未降解内容的自噬空泡的积累增加。Cyld 的基因操作与自噬功能状态的药理学调节相结合的研究表明，CYLD 抑制自噬溶酶体的降解，并促进心肌细胞的死亡。此外，体外和体内的 Cyld 基因获得和/或缺失功能方法表明，CYLD 介导与机械靶蛋白复合物 1（mTORC1）再激活受损和 Ras 基因从大鼠脑 7（Rab7）上调相关的心肌细胞死亡，这两个关键成分对自噬溶酶体降解至关重要。这些结果表明，CYLD 通过抑制心肌细胞中的自噬溶酶体流出，作为心脏病理性重构和功能障碍的一种新的调节因子。从机制上讲，CYLD 很可能通过抑制 mTORC1 的再激活和中断自噬溶酶体中 Rab7 的释放来抑制自噬溶酶体的流出。
