ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruptionof TRAF6-TAK1 interaction

Apoptosis signal-regulating kinase 1 (ASK1) is a mem ber of the MAPKKK fami ly in the JNK and p38 mitogen-activated protein kinase cascades and critica lly involved in stress- and cytokine-induced apoptosis. The transcription f actor nuclear factor-kappaB (NF-kappaB) is a pivotal regulator of immune an d inflammatory responses and exerts anti-apoptotic roles in various cells. Here we show that ASK1 directly interacts with transforming growth factor-b eta -activated kinase 1 (TAK1), another MAPKKK that has been identified as a signaling intermediate in the interleukin 1 (IL-1)-induced NF-kappaB path way as well as the transforming growth factor-beta superfamily-induced JNK/ p38 pathway. Overexpression of ASK1 inhibits IL-1-, TRAF6-, or TAK1-induced , but not NF-kappaB-inducing kinase-induced, NF-kappaB activation. ASK1 dis sociates TAK1 but not NF-kappaB-inducing kinase from TRAF6. Moreover, IL-1- induced complex formation of endogenous TAK1 and TRAF6 was blocked by ASK1 overexpression. It thus appears that the inhibition of NF-kappaB by ASK1 ma y result at least in part from the disruption of the TRAF6 . TAK1 complex f ormation in the IL-1 signaling pathway. These results provide a new insight in the mode of action of MAPKKK family members; two distinct MAPRKKKs in t he same MAP kinase cascades directly interact and exert opposite effects in another signaling pathway, NF-kappaB.