title: Phospho-SXXE/D motif mediated TNF receptor 1-TRADD death domain complex formation for T cell activation and migration.
abstract: 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.
authors: Department of Surgery, Brown University School of Medicine, Providence, RI 02903, USA.
authors: Ying-Jie
authors: YJ
authors: Guan
authors: Zhe
authors: Z
authors: Zhang
authors: Chen
authors: C
authors: Yu
authors: Li
authors: L
authors: Ma
authors: Weiling
authors: W
authors: Hu
authors: Li
authors: L
authors: Xu
authors: Jin-Song
authors: JS
authors: Gao
authors: Chun-Shiang
authors: CS
authors: Chung
authors: Lijuan
authors: L
authors: Wang
authors: Zhong-Fa
authors: ZF
authors: Yang
authors: Loren D
authors: LD
authors: Fast
authors: Alicia S
authors: AS
authors: Chung
authors: Minsoo
authors: M
authors: Kim
authors: Alfred
authors: A
authors: Ayala
authors: Shougang
authors: S
authors: Zhuang
authors: Shusen
authors: S
authors: Zheng
authors: Y Eugene
authors: YE
authors: Chin
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism* / Q000502:physiology
chemical_list: D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D010750:Phosphoproteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D053199:TNF Receptor-Associated Death Domain Protein; C481226:Tradd protein, mouse