title: Mitochondrial Glycerol-3-Phosphate Acyltransferase-Dependent Phospholipid Synthesis Modulates Phospholipid Mass and IL-2 Production in Jurkat T Cells.
abstract: Changes in glycerophospholipid metabolism with age and disease can have a profound effect on immune cell activation and effector function. We previously demonstrated that glycerol-3-phosphate acyltransferase-1, the first and rate limiting step in de novo glycerophospholipid synthesis, plays a role in modulating murine T cell function. The resultant phenotype is characterized by decreased IL-2 production, increased propensity toward apoptosis, and altered membrane glycerophospholipid mass similar to that of an aged T cell. Since T cells in previous experiments were harvested from GPAT-1(-/-) mice, questions remained as to what extent the macro environment of the model influenced the observed cellular phenotype. Therefore, we generated and phenotypically characterized a mitochondrial glycerol-3-phosphate acyltransferase (GPAM) deficient Jurkat T cell. Furthermore, this line was used to probe possible mechanisms by which GPAT-1/GPAM regulates T cell function. We report here that many of the key dysfunctional characteristics of murine GPAT-1(-/-) T cells are recapitulated in the GPAMKD Jurkat T cell. We found striking decreased IL-2 production along with altered phospholipid mass and increased incidence of apoptosis. Since PtdOH is an indirect downstream product of GPAM, we attempted to rescue IL-2 production with PtdOH supplementation; however, this addition did not return IL-2 production to normal levels. Interestingly, we did find significantly decreased Zap-70 phosphorylation following stimulation, suggesting that GPAM deficiency may alter membrane based stimulatory signaling. These data show for the first time that GPAM deficiency results in an inherent defect in Jurkat T cell function and glycerophospholipid composition and that this defect cannot be rescued by addition of exogenous PtdOH.
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, Austin, TX, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Faris
authors.affiliation: Laboratory of Bacteriology, National Institutes of Health, Hamilton, MT, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Weber
authors.affiliation: University of North Dakota, Pharmacology, Physiology, and Therapeutics, Grand Forks, ND, USA.
authors.forename: Drew R
authors.initials: DR
authors.lastname: Seeger
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, Austin, TX, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cavazos
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, Austin, TX, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: de Graffenried
authors.affiliation: University of North Dakota, Pharmacology, Physiology, and Therapeutics, Grand Forks, ND, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Murphy
authors.affiliation: Department of Nutritional Sciences, College of Natural Sciences, Austin, TX, USA. jolly@austin.utexas.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jolly
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D010743:Phospholipids; D005992:Glycerol-3-Phosphate O-Acyltransferase
keywords: Acyl-CoA transferases; Analytical techniques; General area; Immunology; Lipid analysis; Lipid metabolism; Mammalian lipid biochemistry; Metabolism; Phospholipid analysis; Phospholipids; Physiology; Signal transduction; Specific lipids