CMYA5 establishes cardiac dyad architecture and positioning

Fujian Lu, Qing Ma, Wenjun Xie, Carter L. Liou, Donghui Zhang, Mason E. Sweat, Blake D. Jardin, Francisco J. Naya, Yuxuan Guo, Heping Cheng and William T. Pu ()
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Fujian Lu: Boston Children’s Hospital
Qing Ma: Boston Children’s Hospital
Wenjun Xie: Xi’an Jiaotong University
Carter L. Liou: Boston Children’s Hospital
Donghui Zhang: Boston Children’s Hospital
Mason E. Sweat: Boston Children’s Hospital
Blake D. Jardin: Boston Children’s Hospital
Francisco J. Naya: Boston University
Yuxuan Guo: Boston Children’s Hospital
Heping Cheng: Peking University
William T. Pu: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca2+ release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca2+ release.

Date: 2022
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DOI: 10.1038/s41467-022-29902-4

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