P. Juo et al., ESSENTIAL REQUIREMENT FOR CASPASE-8 FLICE IN THE INITIATION OF THE FAS-INDUCED APOPTOTIC CASCADE/, Current biology, 8(18), 1998, pp. 1001-1008
Background: Fas (APO-1/CD95) is a member of the tumor necrosis factor
receptor (TNF-R) family and induces apoptosis when crosslinked with ei
ther Fas ligand or agonistic antibody (Fas antibody), The Fas-Fas liga
nd system has an important role in the immune system where it is invol
ved in the downregulation of immune responses and the deletion of peri
pheral autoreactive T lymphocytes. The intracellular domain of Fas int
eracts with several proteins including FADD (MORT-I), DAXX, RIP, FAF-1
, FAP-I and Sentrin, The adaptor protein FADD can, in turn, interact w
ith the cysteine protease caspase-8 (FLICE/MACH/Mch5). Results: In a g
enetic screen for essential components of the Fas-mediated apoptotic c
ascade, we isolated a Jurkat T lymphocyte cell line deficient in caspa
se-8 that was completely resistant to Fas-induced apoptosis. Complemen
tation of this cell line with wild-type caspase-8 restored Fas-mediate
d apoptosis, Fas activation of multiple caspases and of the stress kin
ases p38 and c-Jun NH2-terminal kinase (JNK) was completely blocked in
the caspase-8-deficient cell line. Furthermore, the cell line was sev
erely deficient in cell death induced by TNF-alpha and was partially d
eficient in cell death induced by ultraviolet irradiation, adriamycin
and etoposide. Conclusions: This study provides the first genetic evid
ence that caspase-8 occupies an essential and apical position in the F
as signaling pathway and suggests that caspase-8 may participate broad
ly in multiple apoptotic pathways.