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Molecular cell v.65 no.4, 2017년, pp.715 - 729.e5   SCI SCIE
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Caspase-8 Acts in a Non-enzymatic Role as a Scaffold for Assembly of a Pro-inflammatory “FADDosome” Complex upon TRAIL Stimulation

Henry, Conor M. (Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland ) ; Martin, Seamus J. (Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland ) ;
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    Summary TRAIL is a potent inducer of apoptosis and has been studied almost exclusively in this context. However, TRAIL can also induce NFκB-dependent expression of multiple pro-inflammatory cytokines and chemokines. Surprisingly, whereas inhibition of caspase activity blocked TRAIL-induced apoptosis, but not cytokine production, knock down or deletion of caspase-8 suppressed both outcomes, suggesting that caspase-8 participates in TRAIL-induced inflammatory signaling in a scaffold role. Consistent with this, introduction of a catalytically inactive caspase-8 mutant into CASP-8 null cells restored TRAIL-induced cytokine production, but not cell death. Furthermore, affinity precipitation of the native TRAIL receptor complex revealed that pro-caspase-8 was required for recruitment of RIPK1, via FADD, to promote NFκB activation and pro-inflammatory cytokine production downstream. Thus, caspase-8 can serve in two distinct roles in response to TRAIL receptor engagement, as a scaffold for assembly of a Caspase-8-FADD-RIPK1 “FADDosome” complex, leading to NFκB-dependent inflammation, or as a protease that promotes apoptosis. Highlights TRAIL induces NFκB-dependent expression of pro-inflammatory cytokines and chemokines Caspase-8 is required for TRAIL-induced inflammatory signaling in a scaffold role Caspase-8 recruits RIPK1 to the TRAIL receptor complex to promote inflammation A TRAIL-induced Caspase-8-FADD-RIPK1 “FADDosome” complex initiates inflammation Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    apoptosis .   Caspase-8 .   cell death .   cytokines .   death receptors .   FADDosome .   NF-κB .   Inflammation .   RIPK1 .   TRAIL.  

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