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

Abstract

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 Fas (APO-1/CD95)-mediated apoptosis. Here, we show that the caspase-4 (TX/ICH-2/ICE rel II)(-like) protease, another member of the caspase family, is also involved in Fas-mediated apoptosis, based upon the observations: (i) caspase-4 is processed in response to an agonistic anti-Fas antibody treatment, (ii) overexpression of a mutant caspase-4 with active site mutations in both p20 and p10 subunits delays Fas-mediated apoptosis, (iii) microinjected anti-caspase-4 antibodies inhibit Fasmediated apoptosis. Together with our observations that the mutant caspase-4 inhibits the Fas-mediated activation of caspase-3(-like) proteases and puri®ed caspase-4 cleaves pro-caspase-3 to generate a subunit of active form, these results suggest that Fas-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.

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

“…Low serum conditions activate apoptosis in immortalized or transformed cell lines (Kulkarni and McCulloch, 1994;Wang and Pandey, 1995;Kawanishi, 1997), probably by depriving the cells of growth factors necessary to promote cell cycle progression (Ohta et al, 1997); cycloheximide is also an e cient inducer of apoptosis in a variety of cell types, perhaps because it blocks the synthesis of one or more proteins essential for the prevention of apoptosis (Martin et al, 1990;Collins et al, 1991;Ledda-Columbano et al, 1992;Ishii et al, 1997); the CD95 (Fas) receptor acts by binding a number of proteins to the`death domain' located on its intracellular portion; etoposide interacts with DNA topoisomerase II and induces DNA strand breaks. The point of convergence of these pathways at the level of eIF4G is most likely the activation of one or more`executioner' caspases (Longthorne and Williams, 1997; Kamada et al, 1997;Cohen, 1997). This is consistent with the ability of the caspase inhibitors (Z-VAD.FMK and Z-DEVD.FMK; Dolle et al, 1994;Fearnhead et al, 1995;Perry et al, 1997;Juo et al, 1997), but not calpain or proteosome inhibitors (data not shown), to block the disappearance of eIF4G regardless of the apoptosis-inducing stimulus.…”

Role of caspases and possible involvement of retinoblastoma protein during TGFβ-mediated apoptosis of human B lymphocytes

“…The amount of the active cleaved form of caspase-2 was maximum after 24 h and it disappeared after 48 h. In contrast, the p17 and p19 forms of caspase-3 were apparent 24 h after stimulation with TGFb and the active p17 form, but not the p19 form, was present after 48 h. This di erent kinetics suggested that TGFb could activate a cascade of di erent caspases similar to that described for Fas-mediated apoptosis (Hirata et al, 1998;Kamada et al, 1997;Susin et al, 1997). However, we were not able to detect, by Western blotting, expression of either proforms or active proteolytic fragments of caspases-1, 4, 6 or 7 in BL41 cells after 30 min and 48 h of activation by TGFb (data not shown).…”

Caspase-4 and caspase-5, members of the ICE/CED-3 family of cysteine proteases, are CrmA-inhibitable proteases

“…In Fas-mediated apoptosis, caspase-1(-like) proteases seem to act downstream of caspase-8 and/or Mch-4 (caspase-10) and upstream of caspase-3(-like) protease (Enari et al, 1996). We have recently shown that a caspase-4(-like) protease is involved in Fas-mediated apoptosis, probably by transducing a death signal directly to caspase-3(-like) proteases (Kamada et al, 1997). Since caspase-4 and caspase-5 cleave pro-caspase-3 to release p12 but not p17, both of which are components of active caspase-3, the generation of p17 might be mediated by other members of caspase family.…”