HTLV-I Tax Protein Binds to MEKK1 to Stimulate IκB Kinase Activity and NF-κB Activation

key members (Baeuerle and Baltimore, 1996; Baldwin, NF-kB, a key regulator of the cellular inflammatory and 1996). Many of the signals leading to the nuclear transloimmune response, is activated by the HTLV-I transcation of NF-kB result in the inducible phosphorylation forming and transactivating protein Tax. We show that and degradation of IkBa (Brown et al., 1995; Chen et Tax binds to the amino terminus of the protein kinase al., 1995). Following phosphorylation of IkBa on serine MEKK1, a component of an IkB kinase complex, and residues 32 and 36, IkBa is ubiquitinated and degraded stimulates MEKK1 kinase activity. Tax expression inby the proteasome leading to the release of free NF-kB creases the activity of IkB kinase b (IKKb) to enhance (Brown et al., 1995; Chen et al., 1995, 1996). phosphorylation of serine residues in IkBa that lead A 700 kDa complex was characterized which contains to its degradation. Dominant negative mutants of both kinases that phosphorylate serine residues 32 and 36 IKKb and MEKK1 prevent Tax activation of the NF-kB in IkBa (Chen et al., 1996; Lee et al., 1997). Kinases in pathway. Furthermore, recombinant MEKK1 stimuthis complex were reported to be activated by TNFa lates IKKb phosphorylation of IkBa. Thus, Tax-meditreatment of cells or in vitro by the addition of either ated increases in NF-kB nuclear translocation result ubiquitin and ubiquitin-conjugating enzymes or the mifrom direct interactions of Tax and MEKK1 leading to togen-activated protein/extracellular signal-regulated kienhanced IKKb phosphorylation of IkBa. nase kinase 1 (MEKK1) (Chen et al., 1996; Lee et al.,