J Biol Chem. 2002 Nov 22;277(47):45162-71. Epub 2002 Sep 4.

The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.External

Micheau, O., Thome, M., Schneider, P., Holler, N., Tschopp, J., Nicholson, D. W., Briand, C., Grutter, M. G.,
--- - Institute of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland.
Death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand receptors, recruit Fas-associated death domain and pro-caspase-8 homodimers, which are then autoproteolytically activated. Active caspase-8 is released into the cytoplasm, where it cleaves various proteins including pro-caspase-3, resulting in apoptosis. The cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein long form (FLIP(L)), a structural homologue of caspase-8 lacking caspase activity because of several mutations in the active site, is a potent inhibitor of death receptor-induced apoptosis. FLIP(L) is proposed to block caspase-8 activity by forming a proteolytically inactive heterodimer with caspase-8. In contrast, we propose that FLIP(L)-bound caspase-8 is an active protease. Upon heterocomplex formation, a limited caspase-8 autoprocessing occurs resulting in the generation of the p43/41 and the p12 subunits. This partially processed form but also the non-cleaved FLIP(L)-caspase-8 heterocomplex are proteolytically active because they both bind synthetic substrates efficiently. Moreover, FLIP(L) expression favors receptor-interacting kinase (RIP) processing within the Fas-signaling complex. We propose that FLIP(L) inhibits caspase-8 release-dependent pro-apoptotic signals, whereas the single, membrane-restricted active site of the FLIP(L)-caspase-8 heterocomplex is proteolytically active and acts on local substrates such as RIP.
PMID: 12215447External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DED Caspase8 Link FLIP Co-immunoprecipitation Raji cell Not used Not specified Not specified 12215447
DED FADD Link FLIP Co-immunoprecipitation Raji cell Not used Not specified Not specified 12215447
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DED Caspase8 Link FLIP Confocal microscopy Apoptosis inhibition 12215447
DED FADD Link FLIP Confocal microscopy Apoptosis inhibition 12215447
(Link: click this icon to show interactions only between the two corresponding DDs)