BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane.
Caspase-8 stably inserts into the mitochondrial outer membrane during extrinsic apoptosis. Inhibition of caspase-8 enrichment on the mitochondria impairs caspase-8 activation and prevents apoptosis. However, the function of active caspase-8 on the mitochondrial membrane remains unknown. In this study, we have identified a native complex containing caspase-8 and BID on the mitochondrial membrane, and showed that death receptor activation by Fas or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced the cleavage of BID (tBID formation) within this complex. tBID then shifted to separate mitochondria-associated complexes that contained other BCL-2 family members, such as BAK and BCL-X(L). We report that cells stabilize active caspase-8 on the mitochondria in order to specifically target mitochondria-associated BID, and that BID cleavage on the mitochondria is essential for caspase-8-induced cytochrome c release. Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria.
Laboratory of Apoptosis and Tumour Metabolism, Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Z T
ZT
Schug
F
F
Gonzalvez
R H
RH
Houtkooper
F M
FM
Vaz
E
E
Gottlieb
D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D008970:Molecular Weight; D050505:Mutant Proteins / Q000378:metabolism; D010444:Peptide Elongation Factor Tu / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C491901:FAS protein, human; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C091648:TUFM protein, human; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; C505530:CASP8 protein, human; D053181:Caspase 8; D010444:Peptide Elongation Factor Tu