title: Glycodelin A triggers mitochondrial stress and apoptosis in T cells by a mechanism distinct and independent of TCR signaling.
abstract: Glycodelin A is one of the progesterone inducible endometrial factors that protect the fetal semiallograft from maternal immune rejection. Our previous studies demonstrate that glycodelin A induces apoptosis in activated T lymphocytes. Here, we report that glycodelin A initiates the intrinsic apoptotic program in T cells. Glycodelin A treatment triggers a stress response leading to mitochondrial membrane permeabilization and activation of initiator caspase 9. The kinetics of mitochondrial depolarization precede onset of DNA fragmentation in both Jurkat cells and peripheral blood T cells treated with glycodelin A. Overexpression of the antiapoptotic protein Bcl-2 is sufficient to protect from glycodelin A-induced cell death. It has been reported earlier that glycodelin A desensitizes T cell receptor (TCR) signaling, probably by its association with the tyrosine phosphatase CD45. Here, we provide evidence that the apoptogenic activity of glycodelin A is not a consequence of this phenomenon. Glycodelin A-induced apoptosis does not depend on components of the TCR signal cascade, including CD45. We observe that glycodelin A is inhibitory to T cells even upon phorbol ester and ionophore stimulation which bypasses the TCR-proximal signaling events, and that glycodelin A treatment does not interfere with T cell activation as evidenced from induction of the activation marker CD69. Thus, glycodelin A initiates mitochondrial stress-mediated apoptosis in T cells by a pathway that is distinct and independent from the TCR signaling pathway.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Swathi
authors.initials: S
authors.lastname: SundarRaj
authors.forename: Debaditya
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Anjali A
authors.initials: AA
authors.lastname: Karande
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology; D053143:Caspase 2 / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D000071816:Glycodelin; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D011257:Pregnancy Proteins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology
chemical_list: D002518:Ceramides; D000071816:Glycodelin; D006023:Glycoproteins; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D015759:Ionomycin; D048055:Mitogen-Activated Protein Kinase 8; D017493:Leukocyte Common Antigens; D053143:Caspase 2; D020782:Matrix Metalloproteinases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium