Involvement of caspase-4(-like) protease in Fas-mediated apoptotic pathway

Proteases of the caspase family, especially caspase-1 (ICE)(-like), caspase-3 (CPP32/Yama/apopain)(-like) and caspase-8 (MACH/FLICE/Mch5) proteases, are implicated in Pas (APO-1/CD95)-mediated apoptosis. Here, we show that the caspase-4 (TX/ICH-2/ICErelII)(-like) protease, another member of the caspase family, is also involved in Pas-mediated apoptosis, based upon the observations: (i) caspase-4 is processed in response to an agonistic anti-Pas antibody treatment, (ii) overexpression of a mutant caspase-4 with active site mutations in both p20 and p10 subunits delays Pas-mediated apoptosis, (iii) microinjected anti-caspase-4 antibodies inhibit Fas-mediated apoptosis. Together with our observations that the mutant caspase-4 inhibits the Pas-mediated activation of caspase-3(-like) proteases and purified caspase-4 cleaves pro-caspase-3 to generate a subunit of active form, these results suggest that Pas-mediated apoptosis is driven by a caspase cascade in which the caspase-4(like) protease transmits a death signal from caspase-8 to caspase-3(-like) proteases probably through directly cleaving pro-caspase-3(-like) proteases.