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

Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated apoptosis, NF-kappaB 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 (DEI)-containing protein, NDED (NF-kappaB-inducible DED-containing protein), depends on the activation of NF-kappaB, The inhibition of NF-kappaB by IKB alpha a natural inhibitor of NF-kappaB, suppressed NDED mRNA expression induced by TNF, The restoration of NDED in NF-kappaB 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-kappaB 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-kappaB.