Induction of apoptosis and ganoderic acid biosynthesis by cAMP signaling in Ganoderma lucidum.
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.
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan. bangjau@mail.cmu.edu.tw.
Bang-Jau
BJ
You
Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan.
Ni
N
Tien
Department of Plant Pathology, National Chung-Hsing University, Taichung, Taiwan.
Miin-Huey
MH
Lee
Department of Pharmacy, China Medical University, Taichung, Taiwan.
Bo-Ying
0000-0001-5510-6513
BY
Bao
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.
Yih-Shyuan
YS
Wu
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan.
Tsung-Chi
TC
Hu
Department of Pharmacy, China Medical University, Taichung, Taiwan. hong@mail.cmu.edu.tw.
Hong-Zin
HZ
Lee
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D017209:Apoptosis; D053898:Biosynthetic Pathways / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D019751:Intramolecular Transferases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020940:Reishi / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012969:Sodium Fluoride / Q000494:pharmacology*; D014315:Triterpenes / Q000378:metabolism*
D010726:Phosphodiesterase Inhibitors; D014315:Triterpenes; C556862:ganoderic acid; D002110:Caffeine; D012969:Sodium Fluoride; D000242:Cyclic AMP; D013186:Farnesyl-Diphosphate Farnesyltransferase; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D015056:1-Methyl-3-isobutylxanthine