Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.
Proteomic analysis identifies key differences in the cardiac interactomes of dystrophin and micro-dystrophin.
复制标题
DOI：
10.1093/hmg/ddab133
复制
发表时间：
2021-06-26
影响因子：
3.5
通讯作者：
Montanaro F
中科院分区：
文献类型：
--
作者：
Wang H;Marrosu E;Brayson D;Wasala NB;Johnson EK;Scott CS;Yue Y;Hau KL;Trask AJ;Froehner SC;Adams ME;Zhang L;Duan D;Montanaro F
ΔR4-R23/ΔCT微肌营养不良蛋白（μDys）是一种小型化的肌营养不良蛋白，目前在杜氏肌营养不良症（DMD）基因治疗试验中评估，用于治疗骨骼肌和心肌疾病。在临床前研究中，μDys有效地挽救了心脏组织病理学，但只能部分恢复心脏功能。为了深入了解可能影响μDys心脏治疗效果的因素，我们通过质谱法比较了小鼠心脏中纯化的抗肌萎缩蛋白和μDys蛋白复合物的组成。我们报告说，与肌营养不良蛋白相比，μDys改变了与α1-和β2-syntrophins以及cavins（一组小窝相关信号蛋白）的关联。特别是，我们发现cavin-1和cavin-4在心肌细胞中的膜定位需要肌营养不良蛋白，并且在DMD模型mdx 5cv小鼠的心脏中被严重破坏。在心脏应激/损伤后，膜相关cavin-4将信号分子ERK招募到小窝，从而激活关键的心脏保护反应。ERK信号传导的评价揭示了在mdx 5cv小鼠心脏中低于生理基线的深度抑制。mdx 5cv小鼠中μDys的表达阻止了心脏组织病理学的发展，但没有拯救cavins的膜定位，也没有使ERK信号正常化。我们的研究提供了第一个比较分析纯化的蛋白质复合物在体内组装的全长肌营养不良蛋白和治疗微肌营养不良蛋白的构建。这揭示了可能导致DMD心肌病的cavins和ERK信号传导的中断。这一新知识对于预防和治疗DMD患者心脏病的持续努力非常重要。
ΔR4-R23/ΔCT micro-dystrophin (μDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, μDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of μDys, we compared by mass spectrometry the composition of purified dystrophin and μDys protein complexes in the mouse heart. We report that compared to dystrophin, μDys has altered associations with α1- and β2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavin-1 and cavin-4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of μDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.
登录
查看更多内容
影响因子：
11.4
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
DOI：
10.1083/jcb.200903053
发表时间：
2009-06-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bastiani M;Liu L;Hill MM;Jedrychowski MP;Nixon SJ;Lo HP;Abankwa D;Luetterforst R;Fernandez-Rojo M;Breen MR;Gygi SP;Vinten J;Walser PJ;North KN;Hancock JF;Pilch PF;Parton RG
通讯作者：
Parton RG
影响因子：
6
作者：
BUSHBY, KMD;GARDNERMEDWIN, D;BHATTACHARYA, SS
通讯作者：
BHATTACHARYA, SS
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
5
作者：
Bostick, Brian;Shin, Jin-Hong;Duan, Dongsheng
通讯作者：
Duan, Dongsheng