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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.

SUBMITTER: Humphreys LM

PROVIDER: S-EPMC7054686 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Humphreys Luke M LM Fox Jennifer P JP Higgins Catherine A CA Majkut Joanna J Sessler Tamas T McLaughlin Kirsty K McCann Christopher C Roberts Jamie Z JZ Crawford Nyree T NT McDade Simon S SS Scott Christopher J CJ Harrison Timothy T Longley Daniel B DB

EMBO reports 20200203 3

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 c ...[more]

PMID: 32009295

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Dataset Information

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

Publications

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

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