Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor [?]-mediated apoptosis by inhibiting caspase-8 activity.
You Z, Ouyang H, Lopatin D, Polver PJ, Wang CY
Laboratory of Molecular Signaling and Apoptosis, the Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.
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 NDEDmRNA 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.
J. Biol. Chem. (2001)
PMID: 11346652 Fulltext – Related articles – Download citation