Binding of the death-domain receptor DR3 to intracellular TRADD and TRAF2 Is independent of its natural ligand, TL1A 2746

Description The TNF-like cytokine TL1A is a type II transmembrane protein that exists in a membrane-bound form or as a soluble homotrimer. TL1A and its receptor, death receptor 3 (DR3), are promising targets for drug discovery in inflammatory bowel diseases (IBD), with multiple clinical trials currently ongoing. Notably, TL1A/DR3 signaling amplifies effector responses in Th1, Th2 and Th17 cells; conversely it is reported to play a role in regulatory T cell (Treg) homeostasis. The prevailing consensus in the scientific literature suggests that TRADD and TRAF2 are recruited to DR3 upon its engagement with TL1A, forming the DR3/TRADD/TRAF2 signaling complex. However, our analysis of the proximal signaling events following TL1A/DR3 binding, conducted through co-IP and ELISA using TF1 and primary human T cells, revealed that while NF-kB activation is dependent upon TL1A-stimulation, the recruitment of TRADD and TRAF2 to the receptor complex is, in fact, independent of TL1A, as the DR3/TRADD/TRAF2 complex preexists in the cells under basal conditions. We now propose a model wherein, DR3/TRADD-associated TRAF2 trimerizes intracellularly following the TL1A binding to DR3. The trimerization of TRAF2 occurs via the C-terminal domains, allowing the N-terminal RING-domain of TRAF2 to dimerize intramolecularly linking distinct TRAF2 trimers, resulting in a hexagonal signaling network with functional E3 ubiquitin ligase activity, thereby rapidly activating the NF-κB pathway. Funding Sources None.