当前位置: X-MOL 学术J. Mol. Cell. Cardiol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
CYLD exaggerates pressure overload-induced cardiomyopathy via suppressing autolysosome efflux in cardiomyocytes.
Journal of Molecular and Cellular Cardiology ( IF 5 ) Pub Date : 2020-06-14 , DOI: 10.1016/j.yjmcc.2020.06.004
Lei Qi 1 , Huimei Zang 2 , Weiwei Wu 2 , Prakash Nagarkatti 3 , Mitzi Nagarkatti 3 , Qinghang Liu 4 , Jeffrey Robbins 5 , Xuejun Wang 6 , Taixing Cui 2
Affiliation  

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.



中文翻译:

CYLD 通过抑制心肌细胞中的自体溶酶体外流来夸大压力超负荷诱导的心肌病。

去泛素化酶 (DUB) 似乎是一类新的心脏稳态和疾病调节剂。然而,心脏中 DUB 介导的信号传导尚不清楚。在此,我们报告了一种新的机制,通过该机制,圆柱瘤病 (CYLD),一种 DUB 介导心脏病理重塑和功能障碍。CYLD (CR-CYLD) 的心肌细胞限制性 (CR) 过表达不会导致严重的健康问题,并且在生理条件下,雌性和雄性小鼠在 1 岁之前几乎不影响心脏功能。然而,CR-CYLD 过表达加剧了压力超负荷 (PO) 诱导的心脏功能障碍,与抑制的心脏肥大相关,并增加了小鼠的心肌细胞凋亡,而与性别无关。在分子水平上,CR-CYLD 过表达增强了 PO 诱导的以赖氨酸 (K)48 连接的泛素链和含有未降解内容物的自噬泡为标志的多泛素化蛋白的增加,同时抑制了自噬通量。通过 CR-ATG7 过表达增强心脏自噬可保护雌性和雄性小鼠免受 PO 诱导的心脏病理重塑和功能障碍。有趣的是,CR-CYLD 过表达将 CR-ATG7 过表达依赖性心脏保护转变为与心脏中含有未降解内容物的自噬空泡的积累增加相关的心肌损伤和功能障碍。Cyld 的遗传操作结合自噬功能状态的药理学调节表明 CYLD 抑制自溶酶体降解并促进心肌细胞的细胞死亡。此外,Cyld 基因获得和/或功能丧失的体外和体内方法表明,CYLD 介导的心肌细胞死亡与雷帕霉素复合物 1 (mTORC1) 的机械靶标的再激活受损和大鼠脑 7 (Rab7) 的 Ras 基因上调相关。自溶酶体降解的两个关键成分。这些结果表明,CYLD 通过抑制心肌细胞中的自体溶酶体流出,作为心脏病理重塑和功能障碍的新型介质。从机制上讲,CYLD 最有可能通过削弱 mTORC1 再激活和中断 Rab7 从心肌细胞中的自溶酶体释放来抑制自溶酶体流出。

更新日期:2020-06-23
down
wechat
bug