Phospho-SXXE/D motif mediated TNF receptor 1-TRADD death domain complex formation for T cell activation and migration.

In TNF-treated cells, TNFR1, TNFR-associated death domain protein (TRADD), Fas-associated death domain protein, and receptor-interacting protein kinase proteins form the signaling complex via modular interaction within their C-terminal death domains. In this paper, we report that the death domain SXXE/D motifs (i.e., S381DHE motif of TNFR1-death domain as well as ...
S215LKD and S296LAE motifs of TRADD-death domain) are phosphorylated, and this is required for stable TNFR1-TRADD complex formation and subsequent activation of NF-κB. Phospho-S215LKD and phospho-S296LAE motifs are also critical to TRADD for recruiting Fas-associated death domain protein and receptor-interacting protein kinase. IκB kinase β plays a critical role in TNFR1 phosphorylation of S381, which leads to subsequent T cell migration and accumulation. Consistently, we observed in inflammatory bowel disease specimens that TNFR1 was constitutively phosphorylated on S381 in those inflammatory T cells, which had accumulated in high numbers in the inflamed mucosa. Therefore, SXXE/D motifs found in the cytoplasmic domains of many TNFR family members and their adaptor proteins may serve to function as a specific interaction module for the α-helical death domain signal transduction.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Movement, Epitopes, T-Lymphocyte, HEK293 Cells, Humans, Inflammation Mediators, Intestinal Mucosa, Jurkat Cells, Lymphocyte Activation, Mice, Mice, Knockout, Molecular Sequence Data, Phosphoproteins, Phosphorylation, Receptors, Tumor Necrosis Factor, Type I, Signal Transduction, T-Lymphocyte Subsets, TNF Receptor-Associated Death Domain Protein
J. Immunol.
Date: Aug. 01, 2011
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