Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
Nat Commun. 2023 Oct 13;14(1):6461. doi: 10.1038/s41467-023-41981-5.
The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.
最常见的遗传性心律失常性心肌病（ACM）的遗传形式是由桥粒斑蛋白-2（PKP2）的突变引起的。通过研究桥粒蛋白 PKP2 的致病缺失突变，我们在这里确定了一种普遍机制，即 PKP2 定位改变限制了肌动球蛋白网络组织和这种无法治疗的疾病中心肌收缩。PKP2 变体的计算建模表明，羧基末端（CT）结构域是稳定 N 端结构域所必需的，这决定了 PKP2 皮质定位和功能。在突变 PKP2 细胞中，相互作用蛋白 MYH10 的表达可挽救肌动球蛋白的紊乱。相反，显性负性 MYH10 突变表达模拟致病性 CT 缺失 PKP2 突变，导致肌动蛋白网络异常和右心室收缩功能障碍。非肌肉肌球蛋白的化学激活剂 4-羟基苯乙酮（4-HAP）也可恢复正常的收缩性。我们的研究结果表明，MYH10 的激活纠正了 PKP2 突变对收缩性心脏收缩的有害影响，这可能对 ACM 治疗具有重要意义。
