Segregation of NF-κB activation through NEMO/IKKγ by Tax and TNFα: Implications for stimulus-specific interruption of oncogenic signaling

Nuclear factor-κB essential modulator (NEMO), also called IKKγ, has been proposed as a 'universal' adaptor of the I-κB kinase (IKK) complex for stimuli such as proinflammatory cytokines, microbes, and the HTLV-I Tax oncoprotein. Currently, it remains unclear whether the many signals that activate NF-κB through NEMO converge identically or differently. We have adopted two approaches to answer this question. First, we generated and targeted intracellularly three NEMO-specific monoclonal antibodies (mAbs). These mAbs produced two distinct intracellular NF-κB inhibition profiles segregating TNFα from Tax activation. Second, using NEMO knockout mouse fibroblasts and 10 NEMO mutants, we found that different regions function in trans either to complement or to inhibit dominantly TNFα, IL-1β, or Tax activation of NF-κB. For instance, NEMO (1-245 amino acids) supported Tax-mediated NF-κB activation, but did not serve TNFα- or IL-1β signaling. Altogether, our findings indicate that while NEMO 'universally' adapts numerous NF-κB activators, it may do so through separable domains. We provide the first evidence that selective targeting of NEMO can abrogate oncogenic Tax signaling without affecting signals used for normal cellular metabolism.