Gpld1, also known as glycosylphosphatidylinositol-specific phospholipase D1, is an enzyme specific for glycosylphosphatidylinositol (GPI) anchors. It exerts its biological functions by cleaving membrane-associated GPI molecules. GPLD1 is abundant in serum, with a concentration of approximately 5-10 µg/mL. It is involved in numerous biological processes and has been implicated in various chronic diseases, including disorders of lipid and glucose metabolism, cancer, and neurological disorders [1].

Exercise-related studies using Gpld1 -/- mice have shown that Gpld1 is crucial for exercise-induced type I interferon (IFN-I) production in the liver. Exercise-produced 3-hydroxybutanoic acid (3-HB) induces Gpld1 expression in the liver, which then blocks the PP2A-IRF3 interaction, enhancing IRF3 activation and IFN-I production, ultimately improving the body's antiviral ability [2]. In intestinal cancer, ablation of Gpld1+ cells combined with 5-fluorouracil treatment attenuated cell viability and regrowth of cancer organoids. GPLD1 cleaves the GPI anchor of serine protease 8 (PRSS8), activating Wnt signalling and promoting epithelial-mesenchymal transition (EMT) in cancer cells. Pharmacological inhibition of GPLD1 suppressed these processes [3].

In conclusion, Gpld1 plays essential roles in multiple biological processes, especially in the context of exercise-mediated immune responses and cancer development. The use of Gpld1 knockout mouse models has provided valuable insights into its functions in antiviral innate immunity and intestinal cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Cao, Jing, Zhou, Anni, Zhou, Zhuoyang, Liu, Hui, Jia, Shaohui. 2023. The role of GPLD1 in chronic diseases. In Journal of cellular physiology, 238, 1407-1415. doi:10.1002/jcp.31041. https://pubmed.ncbi.nlm.nih.gov/37393554/

2. Ren, Tengfei, He, Jiuyi, Zhang, Tingting, Wu, Depei, Zheng, Hui. 2024. Exercise activates interferon response of the liver via Gpld1 to enhance antiviral innate immunity. In Science advances, 10, eadk5011. doi:10.1126/sciadv.adk5011. https://pubmed.ncbi.nlm.nih.gov/38809975/

3. Mizoo, Taisuke, Oka, Takeru, Sugahara, Osamu, Higa, Tsunaki, Nakayama, Keiichi I. . GPLD1+ cancer stem cells contribute to chemotherapy resistance and tumour relapse in intestinal cancer. In Journal of biochemistry, 177, 105-119. doi:10.1093/jb/mvae082. https://pubmed.ncbi.nlm.nih.gov/39743241/