TRAF6 is a signal transducer for interleukin-1

Abstract

Many cytokines signal through different cell-surface receptors to activate the transcription factor NF-kappaB. Members of the TRAF protein family have been implicated in the activation of NF-kappaB by the tumour-necrosis factor (TNF)-receptor superfamily. Here we report the identification of a new TRAF family member, designated TRAF6. When overexpressed in human 293 cells, TRAF6 activates NF-kappaB. A dominant-negative mutant of TRAF6 inhibits NF-kappaB activation signalled by interleukin-1 (IL-1) but not by TNF. IL-1 treatment of 293 cells induces the association of TRAF6 with IRAK, a serine/threonine kinase that is rapidly recruited to the IL-1 receptor after IL-1 induction. These findings indicate that TRAF proteins may function as signal transducers for distinct receptor families and that TRAF6 participates in IL-1 signalling.

Inhibitors of NF-κB signaling: 785 and counting

“…As such, a TRAF2 mutant lacking its N-terminal RING finger domain is a dominant-negative inhibitor of TNFa-(but not IL-1) induced NF-kB activation (Hsu et al, 1996). On the other hand, TRAF6 participates primarily in the IL-1 signal transduction pathway by interacting with the IL-1 receptor, and thus, a dominantnegative mutant of TRAF6 inhibits NF-kB activation signaled by IL-1 but not by TNFa (Cao et al, 1996).…”

From receptors to stress-activated MAP kinases

“…The question marks indicate that direct evidence of these pathways remain to be established (TRAF2), which interacts directly with TNFR-2 (Rothe et al, 1994) but is recruited to TNFR-1 via its interaction with TNFR-1-associated death domain protein (TRADD; Hsu et al, 1995Hsu et al, , 1996b. To date, six members of the TRAF family have been identi®ed (Hu et al, 1994;Rothe et al, 1994;Cheng et al, 1995;Mosialos et al, 1995;Re gnier et al, 1995;Cao et al, 1996;Nakano et al, 1996). All TRAFs contain a conserved C-terminal TRAF domain that is used for homo-or hetero-oligomerization and for interaction with the cytoplasmic regions of the TNFR superfamily.…”

“…All TRAFs contain a conserved C-terminal TRAF domain that is used for homo-or hetero-oligomerization and for interaction with the cytoplasmic regions of the TNFR superfamily. With the exception of TRAF1, all TRAF proteins contain an N-terminal Ring ®nger and several zinc ®nger structures that are critical for their e ector functions (Hu et al, 1994;Rothe et al, 1994;Cheng et al, 1995;Mosialos et al, 1995;Re gnier et al, 1995;Cao et al, 1996;Nakano et al, 1996). Structural and biochemical analyses suggest that TRAFs do not possess enzymatic activity, in turn suggesting that they function as adaptor proteins.…”

MyD genes in negative growth control

“…Consequently, the IL-1 receptor-associated serine/threonine kinase (IRAK) is recruited to the receptor complex, where it is phosphorylated (Cao et al, 1996a). IRAK then dissociates from the receptor complex and interacts with TRAF6, that is required for IL-1-induced NF-kB activation (Cao et al, 1996b). Two other TRAF (TNF-receptor associated factor) proteins, TRAF2 and TRAF5, have been implicated in NF-kB activation by the superfamily of TNF receptors (Aizawa et al, 1997; Duckett et al, 1997; Hsu et al, 1996aHsu et al, , 1997Ishida et al, 1996;Nakano et al, 1996;Rothe et al, 1995), indicating that IL-1 and TNF signaling converge at the level of TRAF molecules.…”