A synthetic lethal screen identifies FAT1 as an antagonist of caspase-8 in extrinsic apoptosis.
The extrinsic apoptosis pathway is initiated by binding of death ligands to death receptors resulting in the formation of the death-inducing signaling complex (DISC). Activation of procaspase-8 within the DISC and its release from the signaling complex is required for processing executor caspases and commiting cell death. Here, we report that the atypical cadherin FAT1 interacts with caspase-8 preventing the association of caspase-8 with the DISC. We identified FAT1 in a genome-wide siRNA screen for synthetic lethal interactions with death receptor-mediated apoptosis. Knockdown of FAT1 sensitized established and patient-derived glioblastoma cell lines for apoptosis transduced by cell death ligands. Depletion of FAT1 resulted in enhanced procaspase-8 recruitment to the DISC and increased formation of caspase-8 containing secondary signaling complexes. In addition, FAT1 knockout cell lines generated by CRISPR/Cas9-mediated genome engineering were more susceptible for death receptor-mediated apoptosis. Our findings provide evidence for a mechanism to control caspase-8-dependent cell death by the atypical cadherin FAT1. These results contribute towards the understanding of effector caspase regulation in physiological conditions.
German Cancer Research Center (DKFZ), Division Signaling and Functional Genomics and Heidelberg University, Department for Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg, Germany.
Dominique
D
Kranz
Michael
M
Boutros
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D008958:Models, Molecular; D034741:RNA, Small Interfering / Q000378:metabolism; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D015820:Cadherins; D061945:Caspase Inhibitors; D053418:Death Domain Receptor Signaling Adaptor Proteins; C502403:FAT1 protein, human; D008024:Ligands; D034741:RNA, Small Interfering; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8