Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity

Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated Apoptosis. NF-kappa B regulates several antiapoptotic molecules including inhibitors of Apoptosis, Bcl-2 Family proteins (A1 and Bcl-X(L))(,) and IEX-IL. Here we report that the expression of a small death effector domain (DED)-containing protein, NDED (NF-kappa B-inducible DED-containing protein), depends on the activation of NF-kappa B. The inhibition of NF-kappa B by I kappa B alpha, a natural inhibitor of NF-kappa B, suppressed NDED mRNA expression induced by TNF. The restoration of NDED in NF-kappa B null cells inhibited TNF-induced Apoptosis. Intriguingly, unlike the Caspase-8 inhibitor cellular FADD-like interleukin-1 beta converting enzyme-inhibitory protein (c-FLIP), NDED suppressed TNF-mediated Apoptosis by inhibiting TNF-induced Caspase-8 enzymatic activity but not the processing of Caspase-8. Furthermore, NDED could not inhibit etoposide-mediated Apoptosis that is independent of Caspase-8 activation. Our results provide the first demonstration that NF-kappa B transcriptionally induces the DED-containing protein to suppress TNF-mediated Apoptosis by inhibiting Caspase-8 activity, which offers new insight into the antiapoptotic mechanism of NF-kappa B.