Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB

Dev Cell. 2012 Sep 11;23(3):611-23. doi: 10.1016/j.devcel.2012.07.013.


The NF-κB transcription factor controls diverse biological processes. According to the classical model, NF-κB is retained in the cytoplasm of resting cells via binding to inhibitory, IκB 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-κB. Sef expression is regulated by the proinflammatory cytokines tumor necrosis factor and interleukin-1, and Sef specifically inhibits "classical" NF-κB (p50:p65) activation by these ligands. Like IκBs, Sef sequesters NF-κB in the cytoplasm of resting cells. However, contrary to IκBs, Sef continues to constrain NF-κB nuclear entry upon ligand stimulation. Accordingly, endogenous Sef knockdown markedly enhances stimulus-induced NF-κB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism*
  • Cytoplasm / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Inflammation*
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells
  • Receptors, Interleukin / metabolism*
  • Signal Transduction*


  • Cytokines
  • IL17RD protein, human
  • NF-kappa B
  • Receptors, Interleukin