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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.

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Affiliations

  • 1. Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
      Authors
    • Henry CM 1
    • Martin SJ 1
    (2 authors)

ORCIDs linked to this article

Molecular Cell, 01 Feb 2017, 65(4):715-729.e5
https://doi.org/10.1016/j.molcel.2017.01.022 PMID: 28212752 

Abstract 

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.

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Read article at publisher's site: https://doi.org/10.1016/j.molcel.2017.01.022

Read article for free, from open access legal sources, via Unpaywall: http://www.cell.com/article/S1097276517300485/pdfUnpaywall

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Investigator award

    Science Foundation Ireland (1)

    Worldwide Cancer Research (1)