Caspase 8 is an initiator caspase that is activated by death receptors to initiate the extrinsic pathway of apoptosis. Caspase 8 activation involves dimerization and subsequent interdomain autoprocessing of caspase 8 zymogens, and recently published work has established that elimination of the autoprocessing site of caspase 8 abrogates its pro-apoptotic function while leaving its proliferative function intact. The observation that the developmental abnormalities of caspase 8-deficient mice are shared by mice lacking the dimerization adapter FADD (Fas-associated death domain) or the caspase paralogue FLIPL [FLICE (FADD-like interleukin 1β-converting enzyme)-inhibitory protein, long form] has led to the hypothesis that FADD-dependent formation of heterodimers between caspase 8 and FLIPL could mediate the developmental role of caspase 8. In the present study, using an inducible dimerization system we demonstrate that cleavage of the catalytic domain of caspase 8 is crucial for its activity in the context of activation by homodimerization. However, we find that use of FLIPL as a partner for caspase 8 in dimerization-induced activation rescues the requirement for intersubunit linker proteolysis in both protomers. Moreover, before processing, caspase 8 in complex with FLIPL does not generate a fully active enzyme, but an attenuated species able to process only selected natural substrates. Based on these results we propose a mechanism of caspase 8 activation by dimerization in the presence of FLIPL, as well as a mechanism of caspase 8 functional divergence in apoptotic and non-apoptotic pathways.
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February 2011
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Research Article|
January 14 2011
FLIPL induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity
Cristina Pop;
Cristina Pop
1
*Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, U.S.A.
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Andrew Oberst;
Andrew Oberst
1
†Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
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Marcin Drag;
Marcin Drag
*Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, U.S.A.
‡Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland
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Bram J. Van Raam;
Bram J. Van Raam
*Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, U.S.A.
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Stefan J. Riedl;
Stefan J. Riedl
*Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, U.S.A.
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Douglas R. Green;
Douglas R. Green
2
†Department of Immunology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, U.S.A.
2Correspondence may be addressed to either of these authors (email douglas.green@stjude.org or gsalvesen@sanfordburnham.org).
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Guy S. Salvesen
Guy S. Salvesen
2
*Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, U.S.A.
2Correspondence may be addressed to either of these authors (email douglas.green@stjude.org or gsalvesen@sanfordburnham.org).
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Publisher: Portland Press Ltd
Received:
October 25 2010
Revision Received:
November 24 2010
Accepted:
November 25 2010
Accepted Manuscript online:
November 25 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 433 (3): 447–457.
Article history
Received:
October 25 2010
Revision Received:
November 24 2010
Accepted:
November 25 2010
Accepted Manuscript online:
November 25 2010
Citation
Cristina Pop, Andrew Oberst, Marcin Drag, Bram J. Van Raam, Stefan J. Riedl, Douglas R. Green, Guy S. Salvesen; FLIPL induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J 1 February 2011; 433 (3): 447–457. doi: https://doi.org/10.1042/BJ20101738
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