INVOLVEMENT OF CASPASE-4(-LIKE) PROTEASE IN FAS-MEDIATED APOPTOTIC PATHWAY

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