TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-B

(IRAK-1) play crucial roles as adaptor molecules in signal transduction of the TLR/IL-1R superfamily, and it is known that expression of these proteins leads to the activation of NF-B in a TNFR-associ-ated factor 6 (TRAF6)-dependent manner. We found in this study, however, that a dominant-neg-ative mutant of TRAF6, lacking the N-terminal RING and zinc-finger domain, did not inhibit IRAK-1-induced activation of NF-B in human embryo kidney 293 cells, although the TRAF6 mu-tant strongly suppressed the MyD88-induced acti-vation. The dominant-negative mutant of TRAF6 did not affect the IRAK-1-induced activation, re-gardless of the expression level of IRAK-1. In con-trast, small interfering RNA silencing of TRAF6 expression inhibited MyD88-induced and IRAK-1-induced activation, and supplementation with the TRAF6 dominant-negative mutant did not restore the IRAK-1-induced activation. Expression of IRAK-1, but not MyD88, induced the oligomer-ization of TRAF6, and IRAK-1 and the TRAF6 dominant-negative mutant were associated with TRAF6. These results indicate that TRAF6 is in-volved but with different mechanisms in MyD88-induced and IRAK-induced activation of NF-B and suggest that TRAF6 uses a distinctive mecha-nism to activate NF-B depending on signals. J