Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis.
Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis.
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DOI：
10.7150/ijbs.69024
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发表时间：
2022
影响因子：
9.2
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Li Z;Wang T;Xin C;Song Y;Kong J;Xu J;Liu Q;Teng Y;Hou N;Cheng X;Yang G;Liu W;Zhou B;Zhang Y;Yang X;Wang J
限制性心肌病(RCM)的分子机制尚不完全清楚。肝细胞生长因子调节的酪氨酸激酶底物(HGS)是运输所需的内体分选(ESCRT)的重要组成部分，它介导蛋白质的降解分选，对维持蛋白质的稳态(蛋白质稳态)至关重要。然而，HGS在RCM中的生理功能和潜在机制尚不清楚。我们推测HGS可能在心脏内稳态中发挥重要作用。建立了心肌细胞特异性HGS基因敲除小鼠，并形成了类似于人RCM的表型。蛋白质组学分析表明，HGS缺乏损害了心肌细胞溶酶体的动态平衡。HGS的缺失破坏了胆固醇的转运和溶酶体的完整性，导致溶酶体储存障碍(LSD)，并伴有自噬小体的异常堆积和蛋白质的聚集。多西环素治疗抑制蛋白聚集可减轻HGS基因敲除小鼠的心脏纤维化和舒张期功能障碍。这些发现揭示了HGS在调节心肌溶酶体稳态和蛋白稳态方面的新的生理作用，表明HGS的缺陷与LSD相关的RCM样心肌病有关。
The molecular mechanisms underlying restrictive cardiomyopathy (RCM) are not fully understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) is a vital element of Endosomal sorting required for transport (ESCRT), which mediates protein sorting for degradation and is crucial for protein homeostasis (proteostasis) maintenance. However, the physiological function and underlying mechanisms of HGS in RCM are unexplored. We hypothesized that HGS may play vital roles in cardiac homeostasis. Cardiomyocyte-specific Hgs gene knockout mice were generated and developed a phenotype similar to human RCM. Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. Loss of Hgs disrupted cholesterol transport and lysosomal integrity, resulting in lysosomal storage disorder (LSD) with aberrant autophagosome accumulation and protein aggregation. Suppression of protein aggregation by doxycycline treatment attenuated cardiac fibrosis, and diastolic dysfunction in Hgs-knockout mice. These findings uncovered a novel physiological role of HGS in regulating cardiac lysosomal homeostasis and proteostasis, suggesting that the deficient HGS contributes to LSD-associated RCM-like cardiomyopathy.
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影响因子：
3.9
作者：
Brodehl, Andreas;Gaertner-Rommel, Anna;Milting, Hendrik
通讯作者：
Milting, Hendrik
影响因子：
24
作者：
Zheng, Hanqiao;Tang, Mingxin;Zheng, Qingwen;Kumarapeli, Asangi R. K.;Horak, Kathleen M.;Tian, Zongwen;Wang, Xuejun
通讯作者：
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影响因子：
9.2
作者：
Chen J;Hou N;Zhang C;Teng Y;Cheng X;Li Z;Ren J;Zeng J;Li R;Wang W;Yang X;Lan Y
通讯作者：
Lan Y
影响因子：
5
作者：
Martin TG;Kirk JA
通讯作者：
Kirk JA
影响因子：
13.3
作者：
Aits, Sonja;Kricker, Jennifer;Jaattela, Marja
通讯作者：
Jaattela, Marja