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

Guo, Cong-ting1; Jardin, Blake D.2; Lin, Jun-sen1; Ambroise, Rachelle L.3; Wang, Ze1; Yang, Lu-zi1; Mazumdar, Neil2; Lu, Fu-jian2,4; Ma, Qing2; Cao, Yang-po5; Liu, Can-zhao6; Li, Kai-long7; Liu, Xu-jie8; Lan, Feng8; Zhao, Ming-ming9,10,11,12; Xiao, Han9,10,11,12; Dong, Er-dan9,10,11,12,13; Pu, William T.2; Guo, Yu-xuan1,10,11,12

2024-07-01

10.1038/s41401-024-01348-y

ACTA PHARMACOLOGICA SINICA   影响因子和分区

1671-4083

1745-7254

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.

proximity proteomics sarcomere Z-disc isoproterenol induced cardiac injury palmdelphin

SCI

英语

其他

National Key R&D Program of China[2022YFA1104800] ; National Natural Science Foundation of China["82222006","82170231"] ; Beijing Nova Program[20220484205] ; Beijing Natural Science Foundation[7232094] ; National Institute of Health["R01HL146634","R01HL163937"] ; Natural Science Foundation of China["82070235","92168113"] ; CAMS Innovation Fund for Medical Sciences[2021-I2M-5-003] ; Haihe Laboratory of Cell Ecosystem Innovation Fund[HH22KYZX0047] ; Guangdong Basic and Applied Basic Research Foundation[2023B1515020103]

Chemistry ; Pharmacology & Pharmacy

Chemistry, Multidisciplinary ; Pharmacology & Pharmacy

WOS:001275228500005

NATURE PUBL GROUP

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Peking Univ, Inst Cardiovasc Sci, Sch Basic Med Sci, Hlth Sci Ctr, Beijing 100191, Peoples R China
2.Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA
3.Harvard Univ, Harvard Coll, Cambridge, MA USA
4.Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China
5.Southern Univ Sci & Technol, Joint Lab Guangdong Hong Kong Univ Vasc Homeostasi, Sch Med, Dept Pharmacol, Shenzhen 518055, Peoples R China
6.Southern Med Univ, Zhujiang Hosp, Translat Med Res Ctr, Dept Cardiol, Guangzhou 510280, Peoples R China
7.Peking Univ, Beijing Key Lab Prot Posttranslat Modificat & Cell, Dept Biochem & Mol Biol, Sch Basic Med Sci,Hlth Sci Ctr, Beijing 100191, Peoples R China
8.Chinese Acad Med Sci, Shenzhen Key Lab Cardiovasc Dis, Fuwai Hosp, Shenzhen 518057, Peoples R China
9.Peking Univ Third Hosp, Inst Vasc Med, Dept Cardiol, Beijing 100191, Peoples R China
10.Peking Univ, State Key Lab Vasc Homeostasis & Remodeling, Beijing 100191, Peoples R China
11.Beijing Key Lab Cardiovasc Receptors Res, Beijing 100191, Peoples R China
12.NHC Key Lab Cardiovasc Mol Biol & Regulatory Pepti, Beijing 100191, Peoples R China
13.Univ Hlth & Rehabil Sci, Qingdao Municipal Hosp, Qingdao Hosp, Res Ctr Cardiopulm Rehabil,Sch Hlth & Life Sci, Qingdao 266071, Peoples R China

Guo, Cong-ting,Jardin, Blake D.,Lin, Jun-sen,et al. In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury[J]. ACTA PHARMACOLOGICA SINICA,2024.

Guo, Cong-ting.,Jardin, Blake D..,Lin, Jun-sen.,Ambroise, Rachelle L..,Wang, Ze.,...&Guo, Yu-xuan.(2024).In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury.ACTA PHARMACOLOGICA SINICA.

Guo, Cong-ting,et al."In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-disc-associated mitigator of isoproterenol-induced cardiac injury".ACTA PHARMACOLOGICA SINICA (2024).