Fas-associated factor-1 mediates chemotherapeutic-induced apoptosis via death effector filament formation

Abstract

Fas-associated factor-1 (FAF1) is a newly introduced member of the Fas death-inducing signaling complex and potentiates Fas-mediated apoptosis. Clinical study has revealed that FAF1 is significantly reduced in gastric carcinomas. The present study demonstrates that FAF1 mediates chemotherapeutic-induced apoptosis via participation in the formation of death effector filament (DEF), a cytoskeleton-like structure found in receptor-independent apoptosis. Overexpression of FAF1 enhanced DEF assembly and cell death induced by chemotherapeutics such as staurosporine (STS), cisplatin (CDDP) and etoposide (VP16). FAF1 sensitized cells to STS, CDDP and VP16 in dose- and time-dependent manner. Introduction of antisense FAF1 construct inhibited DEF assembly and chemotherapeutic-induced apoptosis. Analysis using FAF1 truncates showed that the FAF1 domain interacting with DEDs of FADD and caspase-8 was sufficient to enhance DEF assembly. Confocal microscopy revealed that FAF1 was present in DEFs together with FADD and caspase-8. Collectively, our data provide a molecular mechanism for the chemosensitization by FAF1 (i.e., mediating DEF assembly).