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Co-operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate

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posted on 2016-09-13, 12:09 authored by Michelle A. Hughes, Ian R. Powley, Rebekah Jukes-Jones, Sebastian Horn, Maria Feoktistova, Louise Fairall, John W. R. Schwabe, Martin Leverkus, Kelvin Cain, Marion MacFarlane
The death-inducing signaling complex (DISC) initiates death receptor-induced apoptosis. DISC assembly and activation are controlled by c-FLIP isoforms, which function as pro-apoptotic (c-FLIPL only) or anti-apoptotic (c-FLIPL/c-FLIPS) regulators of procaspase-8 activation. Current models assume that c-FLIP directly competes with procaspase-8 for recruitment to FADD. Using a functional reconstituted DISC, structure-guided mutagenesis, and quantitative LC-MS/MS, we show that c-FLIPL/S binding to the DISC is instead a co-operative procaspase-8-dependent process. FADD initially recruits procaspase-8, which in turn recruits and heterodimerizes with c-FLIPL/S via a hierarchical binding mechanism. Procaspase-8 activation is regulated by the ratio of unbound c-FLIPL/S to procaspase-8, which determines composition of the procaspase-8:c-FLIPL/S heterodimer. Thus, procaspase-8:c-FLIPL exhibits localized enzymatic activity and is preferentially an activator, promoting DED-mediated procaspase-8 oligomer assembly, whereas procaspase-8:c-FLIPS lacks activity and potently blocks procaspase-8 activation. This co-operative hierarchical binding model explains the dual role of c-FLIPL and crucially defines how c-FLIP isoforms differentially control cell fate.

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Citation

Molecular Cell, 2016, 61 (6), pp. 834-849

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

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  • VoR (Version of Record)

Published in

Molecular Cell

Publisher

Elsevier (Cell Press)

issn

1097-2765

eissn

1097-4164

Acceptance date

2016-02-17

Copyright date

2016

Available date

2016-09-13

Publisher version

http://www.sciencedirect.com/science/article/pii/S1097276516001349

Language

en

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