Identification of a cell protein (FIP-3) as a modulator of NF-kB activity and as a target of an adenovirus inhibitor of tumor necrosis factor a-induced apoptosis

FIP-3 (14.7K interacting protein) was discovered during a search for cell proteins that could interact with an adenovirus protein (Ad E3–14.7K) that had been shown to prevent tumor necrosis factor (TNF)-a-induced cytolysis. FIP-3, which contains leucine zippers and a zinc finger domain, inhibits both basal and induced transcriptional activity of NF-kB and causes a late-appearing apoptosis with unique morphologic manifestations. Ad E3–14.7K can partially reverse apoptotic death induced by FIP-3. FIP-3 also was shown to bind to other cell proteins, RIP and NIK, which previously had been described as essential components of TNF-a-induced NF-kB activation. In addition, FIP-3 inhibited activation of NF-kB induced by TNF-a, the TNFR-1 receptor, RIP, NIK, and IKKb, as well as basal levels of endogenous NF-kB in 293 cells. Because the activation of NF-kB has been shown to inhibit apoptosis, FIP-3 appears both to activate a cell-death pathway and to inhibit an NF-kB-dependent sur-