Activation of NF-κB by FADD, Casper, and Caspase-8*

By Wenhui Hu, H. Johnson, H. Shu. Journal of Biological Chemistry, 2000

222 citations recorded by the source corpus.

Fas-associated death domain protein (FADD), caspase-8-related protein (Casper), and caspase-8 are components of the tumor necrosis factor receptor type 1 (TNF-R1) and Fas signaling complexes that are involved in TNF-R1- and Fas-induced apoptosis. Here we show that overexpression of FADD and Casper potently activates NF-κB. In the presence of caspase inhibitors, overexpression of caspase-8 also activates NF-κB. A caspase-inactive point mutant, caspase-8(C360S), activates NF-κB as potently as wild-type caspase-8, suggesting that caspase-8-induced apoptosis and NF-κB activation are uncoupled. NF-κB activation by FADD and Casper is inhibited by the caspase-specific inhibitors crmA and BD-fmk, suggesting that FADD- and Casper-induced NF-κB activation is mediated by caspase-8. FADD, Casper, and caspase-8-induced NF-κB activation are inhibited by dominant negative mutants of TRAF2, NIK, IκB kinase α, and IκB kinase β. A dominant negative mutant of RIP inhibits FADD- and caspase-8-induced but not Casper-induced NF-κB activation. A mutant of Casper and the caspase-specific inhibitors crmA and BD-fmk partially inhibit TNF-R1-, TRADD, and TNF-induced NF-κB activation, suggesting that FADD, Casper, and caspase-8 function downstream of TRADD and contribute to TNF-R1-induced NF-κB activation. Moreover, activation of caspase-8 results in proteolytic processing of NIK, which is inhibited by crmA. When overexpressed, the processed fragments of NIK do not activate NF-κB, and the processed C-terminal fragment inhibits TNF-R1-induced NF-κB activation. These data indicate that FADD, Casper, and pro-caspase-8 are parts of the TNF-R1-induced NF-κB activation pathways, whereas activated caspase-8 can negatively regulate TNF-R1-induced NF-κB activation by proteolytically inactivating NIK.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4a50e13a06dbc9e2bc695ab83521371bee33b656

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Citations in the corpus

• Toll-like receptors. (2003, background): “In addition to the induction of apoptosis, the FADD-dependent pathway mediates the activation of NF-κB and induction of inflammatory gene expression, indicating the possible involvement of FADD in TLR-mediated pathways (287, 288).”