κB-Ras Is a Nuclear-Cytoplasmic Small GTPase That Inhibits NF-κB Activation through the Suppression of Transcriptional Activation of p65/RelA

NF-kappa B is an important transcription factor involved in various biological responses, including inflammation, cell differentiation, and tumorigenesis. kappa B-Ras was identified as an I kappa B-interacting small GTPase and is reported to disturb cytokine-induced NF-kappa B activation. In this study, we established that kappa B-Ras is a novel type of nuclear-cytoplasmic small GTPase that mainly binds to GTP, and its localization seemed to be regulated by its GTP/GDP-binding state. Unexpectedly, the GDP-binding form of the kappa B-Ras mutant exhibited a more potent inhibitory effect on NF-kappa B activation, and this inhibitory effect seemed to be due to suppression of the transactivation of a p65/RelA NF-kappa B subunit. kappa B-Ras suppressed phosphorylation at serine 276 on the p65/RelA subunit, resulting in decreased interaction between p65/RelA and the transcriptional coactivator p300. Interestingly, the GDP-bound kappa B-Ras mutant exhibited higher interactive affinity with p65/RelA and inhibited the phosphorylation of p65/RelA more potently than wild-type kappa B-Ras. Taken together, these findings suggest that the GDP-bound form of kappa B-Ras in cytoplasm suppresses NF-kappa B activation by inhibiting its transcriptional activation.