Stringent negative regulation of the transcription factor NF-êB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKâ are still not clear. Here, we reported that nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFá)-induced NF-êB signaling by inhibiting the phosphorylation of IKKâ. Overexpression of NLK largely blocked TNFá-induced NF-êB activation, p65 nuclear localization and IêBá degradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IêB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKâ and thereby, diminished the IêB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFá-induced activation of NF-êB via disrupting the interaction of TAK1 with IKKâ.
Cell Nucleus Gene Expression Regulation