A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis

Luke M. Humphreys, Jennifer P. Fox, Catherine A. Higgins, Joanna Majkut, Tamas Sessler, Kirsty McLaughlin, Christopher McCann, Jamie Z. Roberts, Nyree T. Crawford, Simon S. McDade, Christopher J. Scott, Timothy Harrison, Daniel B. Longley*

*Corresponding author for this work

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Abstract

The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8) at which it converts from being anti- to pro-apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater. This revised model of DISC assembly also explains why FLIP's recruitment to the TRAIL-R2 DISC is impaired in the absence of caspase-8 despite showing that it can interact with the DISC adaptor protein FADD and why the short FLIP splice form FLIP(S) is the more potent inhibitor of DISC-mediated apoptosis.

Original languageEnglish
Article numbere49254
JournalEMBO Reports
Early online date31 Jan 2020
DOIs
Publication statusEarly online date - 31 Jan 2020

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Death Domain Receptor Signaling Adaptor Proteins
CASP8 and FADD-Like Apoptosis Regulating Protein
Apoptosis
Caspase 8
Death Domain Receptors
Stoichiometry
Chemical activation

Keywords

  • apoptosis
  • caspase-8
  • DISC
  • FLIP
  • TRAIL-R2

Cite this

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title = "A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis",
abstract = "The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8) at which it converts from being anti- to pro-apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater. This revised model of DISC assembly also explains why FLIP's recruitment to the TRAIL-R2 DISC is impaired in the absence of caspase-8 despite showing that it can interact with the DISC adaptor protein FADD and why the short FLIP splice form FLIP(S) is the more potent inhibitor of DISC-mediated apoptosis.",
keywords = "apoptosis, caspase-8, DISC, FLIP, TRAIL-R2",
author = "Humphreys, {Luke M.} and Fox, {Jennifer P.} and Higgins, {Catherine A.} and Joanna Majkut and Tamas Sessler and Kirsty McLaughlin and Christopher McCann and Roberts, {Jamie Z.} and Crawford, {Nyree T.} and McDade, {Simon S.} and Scott, {Christopher J.} and Timothy Harrison and Longley, {Daniel B.}",
year = "2020",
month = "1",
day = "31",
doi = "10.15252/embr.201949254",
language = "English",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Wiley-Blackwell",

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T1 - A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis

AU - Humphreys, Luke M.

AU - Fox, Jennifer P.

AU - Higgins, Catherine A.

AU - Majkut, Joanna

AU - Sessler, Tamas

AU - McLaughlin, Kirsty

AU - McCann, Christopher

AU - Roberts, Jamie Z.

AU - Crawford, Nyree T.

AU - McDade, Simon S.

AU - Scott, Christopher J.

AU - Harrison, Timothy

AU - Longley, Daniel B.

PY - 2020/1/31

Y1 - 2020/1/31

N2 - The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8) at which it converts from being anti- to pro-apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater. This revised model of DISC assembly also explains why FLIP's recruitment to the TRAIL-R2 DISC is impaired in the absence of caspase-8 despite showing that it can interact with the DISC adaptor protein FADD and why the short FLIP splice form FLIP(S) is the more potent inhibitor of DISC-mediated apoptosis.

AB - The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8) at which it converts from being anti- to pro-apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater. This revised model of DISC assembly also explains why FLIP's recruitment to the TRAIL-R2 DISC is impaired in the absence of caspase-8 despite showing that it can interact with the DISC adaptor protein FADD and why the short FLIP splice form FLIP(S) is the more potent inhibitor of DISC-mediated apoptosis.

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KW - caspase-8

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KW - TRAIL-R2

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