1. Upregulated ethanolamine phospholipid synthesis via selenoprotein I is required for effective metabolic reprogramming during T cell activation
- Author
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Vedbar S. Khadka, F. David Horgen, Sharon Rozovsky, Peter R. Hoffmann, Greg S. Gojanovich, Michael P. Marciel, Ellis N.L. Akana, Chi Ma, Melodie A. Williams-Aduja, Mariana Gerschenson, Johann Urschitz, FuKun W. Hoffmann, Stefan Moisyadi, Kathleen E. Page, and Youping Deng
- Subjects
0301 basic medicine ,Male ,AMPK ,Glycosylphosphatidylinositols ,T-Lymphocytes ,Metabolic sensing ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Ethanolamine phosphotransferase ,Glycolysis ,Ethanolamine ,Selenoproteins ,SELENOI, selenoprotein I ,Internal medicine ,Phospholipids ,chemistry.chemical_classification ,Mice, Knockout ,AAG, 1-alkyl, acylglycerol ,TCR, T cell receptor ,Cell biology ,medicine.anatomical_structure ,Ethanolamines ,E2F3, E2F transcription factor 3 ,Female ,Original Article ,Metabolic Networks and Pathways ,CDP, cytidine 5-diphosphate ,GPI, glycosylphosphatidylinositol ,T cell ,DEGs, differentially expressed genes ,CCNE1, cyclin E1 ,PPP, pentose phosphate pathway ,030209 endocrinology & metabolism ,PE, phosphatidylethanolamine ,Selenoprotein ,ER, endoplasmic reticulum ,03 medical and health sciences ,Selenium ,Downregulation and upregulation ,medicine ,Animals ,Metabolomics ,Molecular Biology ,CEPT1, choline/ethanolamine phosphotransferase 1 ,Cell Proliferation ,Phosphatidylethanolamine ,KO, knockout ,Lipogenesis ,Phosphatidylethanolamines ,GPAA1, GPI anchor attachment protein 1 ,Cell Biology ,RC31-1245 ,WT, wild-type ,Metabolic pathway ,AMPK, AMP-activated protein kinase ,030104 developmental biology ,Enzyme ,chemistry ,BUB1, benzimidazoles 1 ,Cancer cell ,DAG, diacylglycerol - Abstract
Objective T cell activation triggers metabolic reprogramming to meet increased demands for energy and metabolites required for cellular proliferation. Ethanolamine phospholipid synthesis has emerged as a regulator of metabolic shifts in stem cells and cancer cells, which led us to investigate its potential role during T cell activation. Methods As selenoprotein I (SELENOI) is an enzyme participating in two metabolic pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, we generated SELENOI-deficient mouse models to determine loss-of-function effects on metabolic reprogramming during T cell activation. Ex vivo and in vivo assays were carried out along with metabolomic, transcriptomic, and protein analyses to determine the role of SELENOI and the ethanolamine phospholipids synthesized by this enzyme in cell signaling and metabolic pathways that promote T cell activation and proliferation. Results SELENOI knockout (KO) in mouse T cells led to reduced de novo synthesis of PE and plasmenyl PE during activation and impaired proliferation. SELENOI KO did not affect T cell receptor signaling, but reduced activation of the metabolic sensor AMPK. AMPK was inhibited by high [ATP], consistent with results showing SELENOI KO causing ATP accumulation, along with disrupted metabolic pathways and reduced glycosylphosphatidylinositol (GPI) anchor synthesis/attachment Conclusions T cell activation upregulates SELENOI-dependent PE and plasmenyl PE synthesis as a key component of metabolic reprogramming and proliferation., Highlights • Selenoprotein I is an enzyme that is upregulated during T cell activation. • Selenoprotein I catalyzes phospholipid synthesis to support proliferation. • Without increased phospholipid synthesis, metabolic shifts are impaired. • Selenoprotein I deficiency causes imbalanced metabolism and ATP accumulation.
- Published
- 2020