penicillic acid :
| 1: J Biol Chem 2003 Feb 21;278(8):5786-93 |
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The mycotoxin penicillic acid inhibits Fas ligand-induced
apoptosis by blocking self-processing of caspase-8 in death-inducing signaling
complex.
Bando M, Hasegawa M, Tsuboi Y, Miyake Y, Shiina M, Ito M, Handa H, Nagai K,
Kataoka T.
Research Center for Experimental Biology and Department of Bioengineering, Tokyo
Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501,
Japan.
Upon engagement with Fas ligand (FasL), Fas rapidly induces recruitment and
self-processing of caspase-8 via the adaptor protein Fas-associated death domain
(FADD), and activated caspase-8 cleaves downstream substrates such as caspase-3.
We have found that penicillic acid (PCA) inhibits FasL-induced apoptosis and
concomitant loss of cell viability in Burkitt's lymphoma Raji cells. PCA
prevented activation of caspase-8 and caspase-3 upon treatment with FasL.
However, PCA did not affect active caspase-3 in FasL-treated cells, suggesting
that PCA primarily blocks early signaling events upstream of caspase-8
activation. FasL-induced processing of caspase-8 was severely impaired in the
death-inducing signaling complex, although FasL-induced recruitment of FADD and
caspase-8 occurred normally in PCA-treated cells. Although PCA inhibited the
enzymatic activities of active recombinant caspase-3, caspase-8, and caspase-9
at similar concentrations, PCA exerted weak inhibitory effects on activation of
caspase-9 and caspase-3 in staurosporine-treated cells but strongly inhibited
caspase-8 activation in FasL-treated cells. Glutathione and cysteine neutralized
an inhibitory effect of PCA on caspase-8, and PCA bound directly to the active
center cysteine in the large subunit of caspase-8. Thus, our present results
demonstrate that PCA inhibits FasL-induced apoptosis by targeting
self-processing of caspase-8.
PMID: 12482880
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