Mechanism Of Casper In Apoptosis And Activation Of NF-κB

Casper is a caspase-8-related molecule critically involved in regulation of death receptor-induced apoptosis. Casper is expressed mostly in a long (Casper-L) or a short (Casper-S) form. Casper-S only contains two N-terminal DEDs, while Casper-L contains two DEDs at its N-terminus and a caspase-like domain at its C-terminus. Casper-L, however, is not a caspase due to its lack of conserved catalytic residues found in all caspases. While it has been widely accepted that Casper-S functions as an inhibitor of death receptor-induced apoptosis, Casper-L has been shown to have both pro- and anti-apoptotic activities and can activate the transcription factor NF-kB. The exact functions of Casper are controversial. To further understand how Casper signals, we searched Casper-interacting proteins by yeast two-hybrid screening. This effort identified p105, an atypical IκB molecule and the precursor of NF-κB subunit p50. Co-immunoprecipitation experiments indicated that Casper interacted with p105 in 293 cells and this interaction was mediated through the C-terminal IκB-like domain (IκBγ) of p105. Overexpression of p 105 and IκBγ inhibited Casper-induced NF-kB activation and potentiated Casper-induced apoptosis. On the other hand, Casper inhibited p105 processing into p50 mediated by its C-terminal caspase-like domain. Furthermore, Casper enhanced the interaction between p105 and caspase-8. Our findings suggest that p105 is critically involved in Casper-mediated regulation of apoptosis and NF-κB activation.