title: TRAF1 phosphorylation on Serine 139 modulates NF-κB activity downstream of 4-1BB in T cells.
abstract: The Tumour Necrosis Factor (TNF) Receptor-associated factor-1 (TRAF1) adaptor protein is a key component in initiating intracellular signalling pathways downstream of TNF receptors (TNFR). More importantly, TRAF1 has a pattern of expression restricted primarily to lymphoid cells and plays an important role in lymphocyte survival. TRAF1 has been shown to be phosphorylated on Serine 139, consequently inhibiting NF-κB activation downstream of TNFR2 when expressed in HeLa cells. We have previously demonstrated that TRAF1 cooperates with the TNFR family member 4-1BB to mediate signalling in T cells. However, the impact of TRAF1 phosphorylation on events downstream of 4-1BB in T cells remained to be defined. Using a proteomics approach we demonstrate that TANK-binding kinase 1 (TBK1) preferentially associates with the TRAF1 Serine 139 to Alanine (S139A) mutant. TBK1 is a kinase that functions upstream of NIK and IKK in the activation of the NF-κB pathway. When TRAF1-deficient CD8 T cells were reconstituted with the TRAF1 S139A mutant, we observed more sustained levels of IκBα degradation in response to 4-1BB stimulation in contrast to cells expressing either TRAF1 wild-type or TRAF1 S139D phospho-mimetic mutant. Together, these findings define the importance of the basal phosphorylation state of the TRAF1 Serine 139 residue in coordinating signalling events downstream of 4-1BB in primary T cells.
authors: Maisonneuve-Rosemont Hospital Research Centre, 5415 l'Assomption Boulevard, Montreal, QC, Canada H1T 2M4.
authors: N A Eustache
authors: NA
authors: Oussa
authors: Youssouf
authors: Y
authors: Soumounou
authors: Laurent
authors: L
authors: Sabbagh
mesh_terms: D000818:Animals; D020672:I-kappa B Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D047990:TNF Receptor-Associated Factor 1; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases