The mycotoxin penicillic acid inhibits Fas ligand-induced apoptosis by blocking self-processing of caspase-8 in death-inducing signaling complex.

Abstract

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.

• Authors: Masashige Bando, Makoto Hasegawa, Yasunori Tsuboi, Yasunobu Miyake, Masashi Shiina, Mika Ito, Hiroshi Handa, Kazuo Nagai, Takao Kataoka
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 8 Pg. 5786-93 (Feb 21 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12482880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• DNA Primers
• Fadd protein, mouse
• Fas Ligand Protein
• Fas-Associated Death Domain Protein
• Fasl protein, mouse
• Membrane Glycoproteins
• Mycotoxins
• Serine
• Casp8 protein, mouse
• Casp9 protein, mouse
• Caspase 8
• Caspase 9
• Caspases
• Glutathione
• Cysteine
• Penicillic Acid

Topics

• Adaptor Proteins, Signal Transducing
• Amino Acid Sequence
• Animals
• Apoptosis (drug effects, physiology)
• Base Sequence
• Carrier Proteins (physiology)
• Caspase 8
• Caspase 9
• Caspases (chemistry, genetics, metabolism)
• Cell Death (drug effects)
• Cysteine (pharmacology)
• DNA Primers
• Fas Ligand Protein
• Fas-Associated Death Domain Protein
• Glutathione (pharmacology)
• Kinetics
• Lymphoma, B-Cell
• Membrane Glycoproteins (antagonists & inhibitors, physiology)
• Mice
• Molecular Sequence Data
• Mycotoxins (toxicity)
• Penicillic Acid (toxicity)
• Polymerase Chain Reaction
• Serine (pharmacology)
• Signal Transduction (drug effects, physiology)
• Tumor Cells, Cultured