SIMPL Is a Tumor Necrosis Factor-specific Regulator of Nuclear Factor-κB Activity*

The IL-1 receptor-associated kinase (IRAK/mPLK) is linked to the regulation of nuclear factor-κB (NF-κB)-dependent gene expression. Here we describe a novel binding partner of IRAK/mPLK that we term SIMPL (signaling molecule that associates with the mouse pelle-like kinase). Overexpression of SIMPL leads to the activation of NF-κB-dependent promoters, and inactivation of SIMPL inhibits IRAK/mPLK as well as tumor necrosis factor receptor type I-induced NF-κB activity. Dominant inhibitory alleles of IκB kinase (IKKα or IKKβ) block the activation of NF-κB by IRAK/mPLK and SIMPL. Furthermore, SIMPL binds IRAK/mPLK and the IKKs in vitro and in vivo. In the presence of antisense mRNA to SIMPL, the physical association between IRAK/mPLK and IKKβ but not IRAK/mPLK and IKKα is greatly diminished. Moreover, dominant-negative SIMPL blocks IKKα- or IKKβ-induced NF-κB activity. These results lead us to propose a model in which SIMPL functions to regulate NF-κB activity by linking IRAK/mPLK to IKKβ/α-containing complexes.AF093135