2. Academic Validation
  3. GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development

GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development

  • Nat Commun. 2025 Apr 8;16(1):3345. doi: 10.1038/s41467-025-58722-5.
Tianyang Zhao # 1,  Kuipei Jin # 2 3,  Xiaodong Wang 1,  Xiong Su 4,  Youjun Wang 5,  Mingming Gao 2,  Wen Luo 6,  Hongyuan Yang 7 8,  Zhongzhou Yang 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China.
  • 2 Laboratory of Lipid Metabolism, Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Cardiovascular Medical Science Center, Hebei Medical University, Shijiazhuang, Hebei, China.
  • 3 Department of Food and Drug Engineering, Shijiazhuang College of Applied Technology, Shijiazhuang, Hebei, PR China.
  • 4 Department of Biochemistry and Biophysics, School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, China.
  • 5 Beijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, PR China.
  • 6 Institute of Modern Biology, Nanjing University, Nanjing, China. luowen@nju.edu.cn.
  • 7 School of Biotechnology and Biomolecular Sciences, the University of New South Wales, Sydney, Australia. Hongyuan.Yang@uth.tmc.edu.
  • 8 Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA. Hongyuan.Yang@uth.tmc.edu.
  • 9 State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China. zhongzhouyang@nju.edu.cn.
  • # Contributed equally.
PMID: 40199910 DOI: 10.1038/s41467-025-58722-5
Abstract

The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate Acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate type-I-interferon response, which affects heart development. Finally, abolishment of the cGAS-STING-type-I-interferon pathway rescues the heart defects of Gpat4 deletion mice. These findings uncover the pivotal role of GPAT4 in the maintenance of ER homeostasis during endocardial and heart development. Meanwhile, this study highlights the importance of the cGAS-STING pathway in cardiac organogenesis.

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