Premium
A synthetic lethal screen identifies FAT 1 as an antagonist of caspase‐8 in extrinsic apoptosis
Author(s) -
Kranz Dominique,
Boutros Michael
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201385686
Subject(s) - german , biology , genomics , functional genomics , center (category theory) , library science , computational biology , genetics , gene , computer science , philosophy , genome , chemistry , linguistics , crystallography
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.