Abstract
A member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family was identified in Drosophila. DTRAF1 contains 7 zinc finger domains followed by a TRAF domain, similar to mammalian TRAFs and other members of the family identified in data bases from Caenorhabditis elegans, Arabidopsis, and Dictyostelium. Analysis of DTRAF1 binding to different members of the human TNF receptor family showed that this protein can interact through its TRAF domain with the p75 neurotrophin receptor and weakly with the lymphotoxin-beta receptor. DTRAF1 can also self-associate and binds to human TRAF1, TRAF2, and TRAF4. Interestingly, DTRAF1 interacts with human cIAP-1 and cIAP-2 but not with Drosophila DIAP-1 and -2. By itself, DTRAF1 did not induce significant NFkappaB activation when overexpressed in mammalian cells, although it specifically increased NFkappaB induction by TRAF6. In contrast, TRAF2-mediated NFkappaB induction was partially inhibited by DTRAF1. Mutants of DTRAF1 lacking the N-terminal region inhibited NFkappaB induction by either TRAF2 or TRAF6. DTRAF1 specifically associated with the regulatory N-terminal domain of Pelle, a Drosophila homolog of the human kinase interleukin-1 receptor-associated kinase (IRAK). Interestingly, though Pelle and DTRAF1 individually were unable to induce NFkappaB in a human cell line, co-expression of Pelle and DTRAF1 resulted in significant NFkappaB activity. Interactions of DTRAF1 with human TRAF-, TNF receptor-, and IAP-family proteins imply strong evolutionary conservation of TRAF protein structure and function throughout Metazoan evolution.
Highlights
Members of the tumor necrosis factor receptor (TNFR)1 superfamily can elicit a wide spectrum of cellular responses, including regulation of cell proliferation, apoptosis, and differentiation [1, 2]
We show that this TNF receptor-associated factors (TRAFs)-family protein is able to bind some mammalian TNFR-family receptors and TRAFs and that it can modulate the NFB pathway in human cells, suggesting strong structural and functional conservation of TRAFs throughout Metazoan evolution
This Drosophila TRAF appears to be the same protein as ours, except that it contains an additional 99 amino acids located at the N terminus of the protein, suggesting that our protein and DTRAF1 arise from a common gene
Summary
Members of the tumor necrosis factor receptor (TNFR) superfamily can elicit a wide spectrum of cellular responses, including regulation of cell proliferation, apoptosis, and differentiation [1, 2]. Specific roles for each of the TRAF-family proteins in the signal transduction pathways regulated by particular TNF-family receptors are beginning to emerge from gene knock-out studies in mice, strongly suggesting cell context dependence (10 –13). Another family of receptor proteins utilizing TRAF proteins as signal transduction mediators is the interleukin-1 receptor/ Toll family. In this report we have identified a Drosophila TRAF protein We show that this TRAF-family protein is able to bind some mammalian TNFR-family receptors and TRAFs and that it can modulate the NFB pathway in human cells, suggesting strong structural and functional conservation of TRAFs throughout Metazoan evolution. We show that Drosophila TRAF (DTRAF-1) is a likely component of the Toll/Spatzle/Pelle signaling complex, based on its ability to interact with Pelle and to regulate Pelle-mediated NFB activation
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