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

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 generated Gpat4 global and tissue-specific knockout mice and identified the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provoked endocardial ER stress response and enhanced ER-mitochondrial (ER-mito) communications, leading to mitochondrial calcium overloading and escape of mitochondrial DNA (mtDNA). As a result, the cGAS-STING pathway was trigged to stimulate type I interferon response, which affected endocardial and myocardial development. Finally, abolishment of the cGAS-STING-type I interferon pathway could rescue the heart defects of Gpat4 deletion mice. These findings uncovered the pivotal role of GPAT4 in the maintenance of ER homeostasis and in fine-tuning ER-Mito contacts during endocardial and heart development. Meanwhile, this study highlights the importance of cGAS-STING pathway in cardiac organogenesis.