1. Glucocorticoid-induced TNF receptor, a costimulatory receptor on naive and activated T cells, uses TNF receptor-associated factor 2 in a novel fashion as an inhibitor of NF-kappa B activation.
- Author
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Esparza EM and Arch RH
- Subjects
- Amino Acid Sequence, Animals, Carrier Proteins physiology, Cell Line, Conserved Sequence, Cysteine Endopeptidases, Cytoplasm chemistry, Cytoplasm metabolism, DNA-Binding Proteins, Down-Regulation genetics, Glucocorticoid-Induced TNFR-Related Protein, Humans, Hydrogen-Ion Concentration, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation genetics, Mice, Mice, Transgenic, Molecular Sequence Data, Nuclear Proteins, Protein Structure, Tertiary genetics, Protein Transport genetics, Protein Transport immunology, Proteins pharmacology, Receptors, Nerve Growth Factor antagonists & inhibitors, Receptors, Nerve Growth Factor metabolism, Receptors, Tumor Necrosis Factor antagonists & inhibitors, Receptors, Tumor Necrosis Factor metabolism, Resting Phase, Cell Cycle genetics, TNF Receptor-Associated Factor 2 metabolism, Transfection, Tumor Necrosis Factor alpha-Induced Protein 3, Tumor Necrosis Factors, Down-Regulation immunology, Lymphocyte Activation immunology, NF-kappa B antagonists & inhibitors, NF-kappa B metabolism, Receptors, Nerve Growth Factor physiology, Receptors, Tumor Necrosis Factor physiology, Resting Phase, Cell Cycle immunology, TNF Receptor-Associated Factor 2 physiology
- Abstract
Glucocorticoid-induced TNFR (GITR) has been implicated as an essential regulator of immune responses to self tissues and pathogens. We have recently shown that GITR-induced cellular events promote survival of naive T cells, but are insufficient to protect against activation-induced cell death. However, the molecular mechanisms of GITR-induced signal transduction that influence physiologic and pathologic immune responses are not well understood. TNFR-associated factors (TRAFs) are pivotal adapter proteins involved in signal transduction pathways of TNFR-related proteins. Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor. GITR-induced activation of NF-kappaB is blocked by A20, an NF-kappaB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs. Interestingly, in contrast with its effects on signaling triggered by other TNFRs, our functional studies revealed that TRAF2 plays a novel inhibitory role in GITR-triggered NF-kappaB activation.
- Published
- 2005
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