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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  FAT 1 interacts with caspase‐8 preventing the association of caspase‐8 with the  DISC . We identified  FAT 1 in a genome‐wide si RNA  screen for synthetic lethal interactions with death receptor‐mediated apoptosis. Knockdown of  FAT 1 sensitized established and patient‐derived glioblastoma cell lines for apoptosis transduced by cell death ligands. Depletion of  FAT 1 resulted in enhanced procaspase‐8 recruitment to the  DISC  and increased formation of caspase‐8 containing secondary signaling complexes. In addition,  FAT 1 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  FAT 1. These results contribute towards the understanding of effector caspase regulation in physiological conditions.

A synthetic lethal screen identifies FAT 1 as an antagonist of caspase‐8 in extrinsic apoptosis