title: The adaptor protein TRADD is essential for TNF-like ligand 1A/death receptor 3 signaling.
abstract: TNFR-associated death domain protein (TRADD) is a key effector protein of TNFR1 signaling. However, the role of TRADD in other death receptor (DR) signaling pathways, including DR3, has not been completely characterized. Previous studies using overexpression systems suggested that TRADD is recruited to the DR3 complex in response to the DR3 ligand, TNF-like ligand 1A (TL1A), indicating a possible role in DR3 signaling. Using T cells from TRADD knockout mice, we demonstrate in this study that the response of both CD4(+) and CD8(+) T cells to TL1A is dependent upon the presence of TRADD. TRADD knockout T cells therefore lack the appropriate proliferative response to TL1A. Moreover, in the absence of TRADD, both the stimulation of MAPK signaling and activation of NF-κB in response to TL1A are dramatically reduced. Unsurprisingly, TRADD is required for recruitment of receptor interacting protein 1 and TNFR-associated factor 2 to the DR3 signaling complex and for the ubiquitination of receptor interacting protein 1. Thus, our findings definitively establish an essential role of TRADD in DR3 signaling.
authors.affiliation: Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yelena L
authors.initials: YL
authors.lastname: Pobezinskaya
authors.forename: Swati
authors.initials: S
authors.lastname: Choksi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morgan
authors.forename: Xiumei
authors.initials: X
authors.lastname: Cao
authors.forename: Zheng-gang
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053199:TNF Receptor-Associated Death Domain Protein / Q000276:immunology* / Q000378:metabolism; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000276:immunology* / Q000378:metabolism
chemical_list: D053219:Receptors, Tumor Necrosis Factor, Member 25; D053199:TNF Receptor-Associated Death Domain Protein; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; C481226:Tradd protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15