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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4070-4078
IMMUNOBIOLOGY
Characterization of caspase-8L: a novel isoform of caspase-8 that
behaves as an inhibitor of the caspase cascade
Daisuke Himeji,
Takahiko Horiuchi,
Hiroshi Tsukamoto,
Kenshi Hayashi,
Takeshi Watanabe, and
Mine Harada
From Medicine and Biosystemic Science, Kyushu
University Graduate School of Medical Sciences; Institute of Genetic
Information, Kyushu University; and Department of Molecular Immunology,
Medical Institute of Bioregulation, Kyushu University; all of Fukuoka,
Japan.
Caspase-8 (Fas-associating protein with death domain-like
interleukin-1 - converting enzyme [FLICE]/MACH/Mch5)
belongs to a family of cysteine proteases presumed to be the apex of
the apoptotic signaling pathways. We recently reported the presence of
a novel isoform of caspase-8, named caspase-8L, generated by the
alternative splicing of human caspase-8 gene, from human peripheral blood lymphocytes by reverse transcriptase-polymerase chain
reaction. We herein report a functional analysis of caspase-8L in the
Fas-mediated apoptotic pathway. Caspase-8L is missing the catalytic
site of caspase-8 but retains 2 N-terminal repeats of the
death-effector domain. The caspase-8L messenger RNA was detected in
various tissues but not in any cell lines examined. In human peripheral
blood lymphocytes, caspase-8L was strongly suggested to be expressed at
the protein level. In MCF-7 cells, caspase-8L transfection itself did
not affect cell viability but instead inhibited the apotosis induced by
the cotransfection of caspase-8 in a dominant negative manner.
Moreover, Fas-mediated apoptosis was inhibited in
caspase-8L-transfected Jurkat cells, which were associated with a
reduction in the caspase-8 catalytic activity. In vitro binding assays
demonstrated that caspase-8L bound to FADD (Fas-associating protein
with death domain) and caspase-8a and blocked the binding of caspase-8
to FADD. In in vivo binding assays, transfected caspase-8L bound to
endogeneous FADD. Thus, caspase-8L acts as an inhibitor of caspase-8 by
interfering with the binding of caspase-8 to FADD and is involved in
the regulation of Fas-mediated apoptosis.
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