Activation of caspases-8 and -10 by FLIP(L).
The first step in caspase activation is transition of the latent zymogen to an active form. For the initiator caspases, this occurs through dimerization of monomeric zymogens at an activating complex. Recent studies have suggested that FLIP(L) [FLICE-like inhibitory protein, long form; FLICE is FADD (Fas-associated death domain protein)-like interleukin-1beta-converting enzyme], previously thought to act solely as an inhibitor of caspase-8 activation, can under certain circumstances function to enhance caspase activation. Using an in vitro induced-proximity assay, we demonstrate that activation of caspases-8 and -10 occurs independently of cleavage of either the caspase or FLIP(L). FLIP(L) activates caspase-8 by forming heterodimeric enzyme molecules with substrate specificity and catalytic activity indistinguishable from those of caspase-8 homodimers. Significantly, the barrier for heterodimer formation is lower than that for homodimer formation, suggesting that FLIP(L) is a more potent activator of caspase-8 than is caspase-8 itself.
Boatright
Kelly M
KM
Program in Apoptosis and Cell Death Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Deis
Cristina
C
Denault
Jean-Bernard
JB
Sutherlin
Daniel P
DP
Salvesen
Guy S
GS
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D004789:Enzyme Activation / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells / Q000201:enzymology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; D020169:Caspases; C506438:CASP10 protein, human