Set Is an Inhibitor of Proinflammatory Cytokine Signaling, Acting by Cytoplasmic Sequestration of NF-κB

The NF-kappa B transcription factor controls diverse biological processes. According to the classical model, NF-kappa B is retained in the cytoplasm of resting cells via binding to inhibitory, I kappa B proteins and translocates into the nucleus upon their ligand-induced degradation. Here we reveal that Sef, a known tumor suppressor and inhibitor of growth factor signaling, is a spatial regulator of NF-kappa B. Sef expression is regulated by the proinflammatory cytokines tumor necrosis factor and interleukin-1, and Sef specifically inhibits "classical" NF-kappa B (p50:p65) activation by these ligands. Like I kappa Bs, Sef sequesters NF-kappa B in the cytoplasm of resting cells. However, contrary to I kappa Bs, Sef continues to constrain NF-kappa B nuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown markedly enhances stimulus-induced NF-kappa B nuclear translocation and consequent activity. This study establishes Sef as a feedback antagonist of proinflammatory cytokines and highlights its potential to regulate the crosstalk between proinflammatory cytokine receptors and receptor tyrosine kinases.