北京大学郭宇轩等研究人员合作发现发现，体内近距离蛋白质组学发现palmdelphin （PALMD）是异丙肾上腺素诱导心脏损伤的Z盘相关缓解因子。相关论文于2024年7月23日在线发表在《中国药理学报》杂志上。

研究人员建立了一种腺相关病毒（AAV）传递、心肌细胞特异性、邻近标记的方法，以在体内表征Z盘蛋白质组。研究人员发现palmdelphin （PALMD）是成年小鼠心肌细胞和人类多能干细胞衍生的心肌细胞中的一种新型Z盘相关蛋白。生殖系和心肌细胞特异性Palmd敲除小鼠在基础状态下表现正常，但在长期异丙肾上腺素处理后表现出心脏肥大受损和心脏损伤加重。

相比之下，心肌细胞特异性PALMD过表达足以减轻异丙肾上腺素引起的心脏损伤。PALMD缺失扰乱了横小管（T-tubule）-肌浆网（SR）超微结构，形成了Z盘相关的连接膜复合体（JMC），这对钙处理和心脏功能至关重要。

这些表型与NEXN（一种对Z盘和JMC结构和功能至关重要的关键Z盘相关蛋白）的减少有关。PALMD与NEXN相互作用并增强其蛋白稳定性，而Nexn mRNA水平未受影响。基于AAV的NEXN补充可以挽救PALMD缺失小鼠在异丙肾上腺素处理下加重的心脏损伤。总之，这项研究发现PALMD是一种潜在的心肌保护靶点，并突出了体内邻近蛋白质组学作为提名调节心脏病理发生新参与者的强大方法。

据悉，Z盘是心肌细胞的核心超微结构组织者，调节着心脏病理发生的多个方面。然而，Z盘相关成分的全面蛋白质组图谱仍不完整。

附：英文原文

Title: In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury

Author: Guo, Cong-ting, Jardin, Blake D., Lin, Jun-sen, Ambroise, Rachelle L., Wang, Ze, Yang, Lu-zi, Mazumdar, Neil, Lu, Fu-jian, Ma, Qing, Cao, Yang-po, Liu, Can-zhao, Li, Kai-long, Liu, Xu-jie, Lan, Feng, Zhao, Ming-ming, Xiao, Han, Dong, Er-dan, Pu, William T., Guo, Yu-xuan

Issue&Volume: 2024-07-23

Abstract: Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.

DOI: 10.1038/s41401-024-01348-y

Source: https://www.nature.com/articles/s41401-024-01348-y