Abstract.
Members of the tumor necrosis factor receptor (TNFR) family regulate the activation, differentiation, and function of many cell types, including cells of the immune system. TNFR-associated factors (TRAFs) function as adapter molecules controlling signaling pathways triggered by TNFR family members, such as activation of nuclear factor κB (NF-κB). Despite intensive research, the function of TRAF4 in signaling pathways triggered by TNFR-related proteins remains enigmatic. Intriguingly, our functional studies indicated that TRAF4 augments NF-κB activation triggered by glucocorticoid-induced TNFR (GITR), a receptor expressed on T cells, B cells, and macrophages. Further analyses revealed that TRAF4-mediated NF-κB activation downstream of GITR depends on a previously mapped TRAF-binding site in the cytoplasmic domain of the receptor and is inhibited by the cytoplasmic protein A20. GITR is thought to inhibit the suppressive function of regulatory T cells (Treg cells) and to promote activation of T cells. Taken together, our studies provide the first indications that TRAF4 elaborates GITR signaling and suggest that TRAF4 can modulate the suppressive functions of Treg cells.
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Received 20 September 2004; received after revision 8 October 2004; accepted 18 October 2004
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Esparza, E.M., Arch, R.H. TRAF4 functions as an intermediate of GITR-induced NF-κB activation. CMLS, Cell. Mol. Life Sci. 61, 3087–3092 (2004). https://doi.org/10.1007/s00018-004-4417-0
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DOI: https://doi.org/10.1007/s00018-004-4417-0