Sef Is an Inhibitor of Proinflammatory Cytokine Signaling, Acting by Cytoplasmic Sequestration of NF-[kappa]B

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.