title: Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-κB.
abstract: 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.
authors.affiliation: Department of Biology, Technion, Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Fuchs
authors.forename: Michal
authors.initials: M
authors.lastname: Brunwasser
authors.forename: Sasha
authors.initials: S
authors.lastname: Haif
authors.forename: Jumana
authors.initials: J
authors.lastname: Haddad
authors.forename: Boris
authors.initials: B
authors.lastname: Shneyer
authors.forename: Orit
authors.initials: O
authors.lastname: Goldshmidt-Tran
authors.forename: Lina
authors.initials: L
authors.lastname: Korsensky
authors.forename: Mona
authors.initials: M
authors.lastname: Abed
authors.forename: Simona
authors.initials: S
authors.lastname: Zisman-Rozen
authors.forename: Lilach
authors.initials: L
authors.lastname: Koren
authors.forename: Yaron
authors.initials: Y
authors.lastname: Carmi
authors.forename: Ron
authors.initials: R
authors.lastname: Apte
authors.forename: Ruey-Bing
authors.initials: RB
authors.lastname: Yang
authors.forename: Amir
authors.initials: A
authors.lastname: Orian
authors.forename: Jacob
authors.initials: J
authors.lastname: Bejar
authors.forename: Dina
authors.initials: D
authors.lastname: Ron
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018123:Receptors, Interleukin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C477526:IL17RD protein, human; D016328:NF-kappa B; D018123:Receptors, Interleukin