CASH, A NOVEL CASPASE HOMOLOG WITH DEATH EFFECTOR DOMAINS

CASP-8 and CASP-10, members of a cysteine protease family that partici pates in apoptosis, interact with MORT1/FADD, an adapter protein in th e CD120a (p55 tumor necrosis factor receptor), and CD95 (Fas/Apo-1) de ath-inducing signaling pathways, through a shared N-terminal sequence motif, the death effector domain. We report cloning of two splice vari ants of a novel protein, CASH, that contain two N-terminal death effec tor domains and can bind through them to each other, to MORT1/FADD, to CASP-8, and to CASP-10. The unique C-terminal part of the longer vari ant shows marked sequence homology to the caspase protease region yet lacks several of the conserved caspase active site residues, suggestin g that it is devoid of cysteine protease activity. Overexpression of t he short CASH splice variant strongly inhibited cytotoxicity induction by CD120a and CD95. Expression of the longer variant, while inhibitin g cytotoxicity in HeLa cells, had a marked cytocidal effect in 293 cel ls that could be shown to involve its protease homology region. The fi ndings suggest that CASH acts as an attenuator and/or initiator in CD9 5 and CD120a signaling for cell death.