Abstract
Apoptosis is an essential physiological process that controls many important biological functions. However, apoptosis signaling in relation to secondary metabolite biosynthesis in plants and fungi remains a mystery. The fungus Ganoderma lucidum is a popular herbal medicine worldwide, but the biosynthetic regulation of its active ingredients (ganoderic acids, GAs) is poorly understood. We investigated the role of 3′,5′-cyclic adenosine monophosphate (cAMP) signaling in fungal apoptosis and GA biosynthesis in G. lucidum. Two phosphodiesterase inhibitors (caffeine and 3-isobutyl-1-methylxanthine, IBMX) and an adenylate cyclase activator (sodium fluoride, NaF) were used to increase intracellular cAMP levels. Fungal apoptosis was identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and a condensed nuclear morphology. Our results showed that GA production and fungal apoptosis were induced when the mycelium was treated with NaF, caffeine, or cAMP/IBMX. Downregulation of squalene synthase and lanosterol synthase gene expression by cAMP was detected in the presence of these chemicals, which indicates that these two genes are not critical for GA induction. Transcriptome analysis indicated that mitochondria might play an important role in cAMP-induced apoptosis and GA biosynthesis. To the best of our knowledge, this is the first report to reveal that cAMP signaling induces apoptosis and secondary metabolite production in fungi.
Highlights
Ganoderma lucidum, a traditional Chinese herb, has been used to treat various human diseases such as cancer, inflammation, chronic hepatitis, heart disease, and hypertension for thousands years in Asia[1]
To investigate the role of cyclic adenosine monophosphate (cAMP) signaling in fungal apoptosis, the mycelium of G. lucidum was treated with caffeine and NaF
Fungal apoptosis was identified by the presence of double-stranded DNA degradation and changes in nuclear morphology detected by the transferase mediated dUTP nick end labeling (TUNEL) assay and DAPI (4′,6-diamidino-2-phenylindole) staining, respectively
Summary
A traditional Chinese herb, has been used to treat various human diseases such as cancer, inflammation, chronic hepatitis, heart disease, and hypertension for thousands years in Asia[1]. G. lucidum has the potential to be used as a model system for studying the regulation of secondary metabolite biosynthesis in Chinese herbal medicines. The physiological roles of apoptosis have been well investigated in a range of organisms in different contexts, but its effects on secondary metabolite biosynthesis have not been explored much. Our previous study has indicated that aspirin is able to induce apoptosis and GA production in G. lucidum[14]. The mechanisms controlling this phenomenon remain unknown, as do the mechanisms that coordinate apoptosis and secondary metabolite biosynthesis. The role of 3′,5′-cyclic adenosine monophosphate (cAMP) signaling in apoptosis and GA biosynthesis was investigated. Transcriptome analysis was further conducted to investigate the global transcriptional changes associated with cAMP-induced apoptosis and GA biosynthesis
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