GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58722-5 |
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| author | Tianyang Zhao Kuipei Jin Xiaodong Wang Xiong Su Youjun Wang Mingming Gao Wen Luo Hongyuan Yang Zhongzhou Yang |
| author_facet | Tianyang Zhao Kuipei Jin Xiaodong Wang Xiong Su Youjun Wang Mingming Gao Wen Luo Hongyuan Yang Zhongzhou Yang |
| author_sort | Tianyang Zhao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e6ae1f241e1a4840ae4e83bd4587c8c1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e6ae1f241e1a4840ae4e83bd4587c8c12025-08-20T02:17:13ZengNature PortfolioNature Communications2041-17232025-04-0116111410.1038/s41467-025-58722-5GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart developmentTianyang Zhao0Kuipei Jin1Xiaodong Wang2Xiong Su3Youjun Wang4Mingming Gao5Wen Luo6Hongyuan Yang7Zhongzhou Yang8State 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 SchoolLaboratory 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, ShijiazhuangState 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 SchoolDepartment of Biochemistry and Biophysics, School of Life Sciences, Suzhou Medical College of Soochow UniversityBeijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal UniversityLaboratory 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, ShijiazhuangInstitute of Modern Biology, Nanjing UniversitySchool of Biotechnology and Biomolecular Sciences, the University of New South WalesState 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 SchoolAbstract 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.https://doi.org/10.1038/s41467-025-58722-5 |
| spellingShingle | Tianyang Zhao Kuipei Jin Xiaodong Wang Xiong Su Youjun Wang Mingming Gao Wen Luo Hongyuan Yang Zhongzhou Yang GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development Nature Communications |
| title | GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| title_full | GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| title_fullStr | GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| title_full_unstemmed | GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| title_short | GPAT4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| title_sort | gpat4 sustains endoplasmic reticulum homeostasis in endocardial cells and safeguards heart development |
| url | https://doi.org/10.1038/s41467-025-58722-5 |
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