Journal of Biological Chemistry
Volume 279, Issue 4, 23 January 2004, Pages 2544-2549
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Mechanisms of Signal Transduction
Fas-associated Factor-1 Inhibits Nuclear Factor-κB (NF-κB) Activity by Interfering with Nuclear Translocation of the RelA (p65) Subunit of NF-κB*

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Fas-associated factor-1 (FAF1) is a Fas-binding pro-apoptotic protein that is a component of the death-inducing signaling complex in Fas-mediated apoptosis. Here, we show that FAF1 is involved in negative regulation of NF-κB activation. Overexpression of FAF1 decreased the basal level of NF-κB activity in 293 cells. NF-κB activation induced by tumor necrosis factor (TNF)-α, interleukin-1β, and lipopolysaccharide was also inhibited by FAF1 overexpression. Moreover, FAF1 suppressed NF-κB activation induced by transducers of diverse NF-κB-activating signals such as TNF receptor-associated factor-2 and -6, MEKK1, and IκB kinase-β as well as NF-κB p65, one of the end point molecules in the NF-κB activation pathway, suggesting that NF-κB p65 might be a target molecule upon which FAF1 acts. Subsequent study disclosed that FAF1 physically interacts with NF-κB p65 and that the binding domain of FAF1 is the death effector domain (DED)-interacting domain (amino acids 181–381), where DEDs of the Fas-associated death domain protein and caspase-8 interact. The NF-κB activity-modulating potential of FAF1 was also mapped to the DED-interacting domain. Finally, overexpression of FAF1 prevented translocation of NF-κB p65 into the nucleus and decreased its DNA-binding activity upon TNFα treatment. This study presents a novel function of FAF1, in addition to the previously known function as a component of the Fas death-inducing signaling complex, i.e. NF-κB activity suppressor by cytoplasmic retention of NF-κB p65 via physical interaction.

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This work was supported by Ministry of Science & Technology and Korea Science and Engineering Foundation through the Research Center for Biomedicinal Resources of PaiChai University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.