Development of novel anti-inflammatory drugs on the basis of prostaglandin A1 structure

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The IKK-related kinase NAK contributes to the activation of NF-κB-dependent gene transcription. Here we identify NAP1 (NAK-associated protein 1), a protein that interacts with NAK and its relative IKKε. NAP1 activates NAK and facilitates its oligomerization. Interestingly, the NAK-NAP1 complex itself effectively phosphorylated serine 536 of the p65/RelA subunit of NF-κB and this activity was stimulated by tumor necrosis factor-α (TNF-α). Overexpression of NAP1 specifically enhanced cytokine-induction of an NF-κB-dependent, but not AP-1-dependent reporter. Depletion of NAP1 reduced NF-κB-dependent gene expression and sensitized cells to TNF-α-induced apoptosis. These results define NAP1 as an activator of IKK-related kinases and suggest that the NAK-NAP1 complex may protect cells from TNF-α-induced apoptosis by promoting NF-κB activation.