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c‐FLIP L is a dual function regulator for caspase‐8 activation and CD95‐mediated apoptosis
Author(s) -
Chang David W.,
Xing Zheng,
Pan Yi,
AlgecirasSchimnich Alicia,
Barnhart Bryan C.,
YaishOhad Shoshanit,
Peter Marcus E.,
Yang Xiaolu
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf356
Subject(s) - biology , apoptosis , microbiology and biotechnology , regulator , caspase , fas receptor , function (biology) , caspase 8 , dual function , caspase 3 , caspase 9 , biochemistry , programmed cell death , gene , contouring , engineering , engineering drawing
Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor‐mediated homo‐oligomerization of initiator procaspases. Here we show that c‐FLIP L , a protease‐deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death‐inducing signaling complex (DISC) and potently promotes procaspase‐8 activation through hetero‐dimerization. c‐FLIP L exerts its effect through its protease‐like domain, which associates efficiently with the procaspase‐8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c‐FLIP L at physiologically relevant levels enhances procaspase‐8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c‐FLIP L expression results in inhibition of apoptosis. c‐FLIP L acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c‐FLIP L defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.