In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury
Cong-ting Guo1,
Blake D. Jardin2,
Jun-sen Lin1,
Rachelle L. Ambroise3,
Ze Wang1,
Lu-zi Yang1,
Neil Mazumdar2,
Fu-jian Lu2,4,
Qing Ma2,
Yang-po Cao5,
Can-zhao Liu6,
Kai-long Li7,
Xu-jie Liu8,
Feng Lan8,
Ming-ming Zhao9,10,11,
Han Xiao9,10,11,
Er-dan Dong9,10,11,12,
William T. Pu2,
Yu-xuan Guo1,10,11
1 School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
2 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
3 Harvard College, Harvard University, Cambridge, MA, USA
4 Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
5 Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
6 Department of Cardiology, Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China
7 Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
8 Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen 518057, China
9 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China
10 State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
11 Beijing Key Laboratory of Cardiovascular Receptors Research; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing 100191, China
12 Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, China
Correspondence to: William T. Pu: william.pu@cardio.chboston.org, Yu-xuan Guo: william.pu@cardio.chboston.org,
DOI: 10.1038/s41401-024-01348-y
Received: 25 March 2024
Accepted: 28 June 2024
Advance online: 23 July 2024
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.
