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.
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.
Esparza
Edward M
EM
Department of Medicine, School of Medicine, Washington University, St. Louis, MO 63110, USA.
Arch
Robert H
RH
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D017124:Conserved Sequence; D003546:Cysteine Endopeptidases; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009687:Nuclear Proteins; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011506:Proteins / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology*; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D048069:Tumor Necrosis Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C491405:TNFRSF18 protein, human; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse