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

Nuclear factor kappa B (NF-kappa B)-inducing kinase (NIK) participates in t he activation of NF-kappa B, a family of eukaryotic transcription factors t hat mediate cell growth and transformation. NIK activates the I kappa B kin ase both in vivo and in vitro, although how the activity of NIK is regulate d has remained unclear. Here we show that the N-terminal region of NIK cont ains 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 marke d enhancement of NIK function. We further demonstrate that the N-terminal N RD interacts with the C-terminal region of NIK, thereby inhibiting the bind ing of NIK to its substrate I kappa B kinase. Consistently, when expressed alone, the NRD potently inhibits NIK-mediated NF-kappa B signaling. These r esults provide a new insight into the mechanism of NIK regulation.