Negative regulation of the nuclear factor κB-inducing kinase by a cis-acting domain

Nuclear factor kappa B (NF-kappa B)-inducing kinase (NIK) participates in the activation of NF-kappa B, a family of eukaryotic transcription factors that mediate cell growth and transformation. NIK activates the I kappa B kinase both in vivo and in vitro, although how the activity of NIK is regulated has remained unclear. Here we show that the N-terminal region of NIK contains a negative-regulatory domain (NRD), which is composed of a basic motif and a proline-rich repeat motif. Deletion of these motifs leads to a marked enhancement of NIK function. We further demonstrate that the N-terminal NRD interacts with the C-terminal region of NIK, thereby inhibiting the binding of NIK to its substrate I kappa B kinase. Consistently, when expressed alone, the NRD potently inhibits NIK-mediated NF-kappa B signaling. These results provide a new insight into the mechanism of NIK regulation.