Phospho-SXXE/D Motif Mediated TNFR1-TRADD Death Domain Complex Formation For T Cell Activation And Migration

In TNF treated cells, TNFRl, TRADD, FADD, and RIP proteins form the complex for signaling via modular interaction within their C-terminal death domains. Here we report that the death domain "SXXE/D" motifs, i.e., S381DHE motif of TNFR1-death domain, S215LKD and S296LAE motifs of TRADD-death domain are phosphorylated and required for a stable TNFRl-TRADD complex formation and subsequent NF-κB activation. Phospho-S215LKD and phospho-S296LAE motifs are also critical for TRADD to recruit FADD and RIP. IKKβ plays a critical role in TNFRl phosphorylation on S381, leading to subsequent T cell migration and accumulation. Consistently, in IBD, TNFRl is constitutively phosphorylated on S381in those inflammatory T cells that are highly accumulated in inflamed mucosa. Therefore, SXXE/D motifs found in the cytoplasmic domains of many TNFR family members and their adaptor proteins may function as a specific interaction module for the a-helical death domain signal transduction.