Dataset Information

Transcriptome Analysis Reveals the Flexibility of Cordycepin Network in Cordyceps militaris Activated by L-Alanine Addition.

ABSTRACT: Cordycepin, isolated from the traditional medicinal fungus Cordyceps militaris, has gained much attention due to its various clinical functions. Previous reports of L-alanine addition could significantly improve cordycepin production, but the molecular mechanism remains unknown. In this study, transcriptome analysis of C. militaris with doubled cordycepin production induced by L-alanine addition provides an insight into the flexibility of the cordycepin network. The biopathways of energy generation and amino acid conversion were activated so that cordycepin substrate generation was consequently improved. Specific genes of rate-limiting enzymes in these pathways, as well as related transcription factors, were figured out. Two key Zn2Cys6-type transcription factors CmTf1 and CmTf2 were verified to play the roles of doubling the cordycepin production by overexpression of their coding genes in C. militaris wild type. These results provide a complete map of the cordycepin network in C. militaris with a distinct understanding of the flexibility of joints, giving a better foundation for increasing cordycepin yield and strain breeding in the future.

SUBMITTER: Chen BX

PROVIDER: S-EPMC7193312 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Transcriptome Analysis Reveals the Flexibility of Cordycepin Network in Cordyceps militaris Activated by L-Alanine Addition.

Chen Bai-Xiong BX Wei Tao T Xue Ling-Na LN Zheng Qian-Wang QW Ye Zhi-Wei ZW Zou Yuan Y Yang Yi Y Yun Fan F Guo Li-Qiong LQ Lin Jun-Fang JF

Frontiers in microbiology 20200424

Cordycepin, isolated from the traditional medicinal fungus Cordyceps militaris, has gained much attention due to its various clinical functions. Previous reports of L-alanine addition could significantly improve cordycepin production, but the molecular mechanism remains unknown. In this study, transcriptome analysis of C. militaris with doubled cordycepin production induced by L-alanine addition provides an insight into the flexibility of the cordycepin network. The biopathways of ...[more]

PMID: 32390960

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Project description:Hypocrealean entomopathogenic fungi (EPF) (Sordariomycetes, Ascomycota) are natural regulators of insect populations in terrestrial environments. Their obligately-killing life-cycle means that there is likely to be strong selection pressure for traits that allow them to evade the effects of the host immune system. In this study, we quantified the effects of cordycepin (3'-deoxyadenosine), a secondary metabolite produced by Cordyceps militaris (Hypocreales, Cordycipitaceae), on insect susceptibility to EPF infection and on insect immune gene expression. Application of the immune stimulant curdlan (20 µg ml-1, linear beta-1,3-glucan, a constituent of fungal cell walls) to Drosophila melanogaster S2r+ cells resulted in a significant increase in the expression of the immune effector gene metchnikowin compared to a DMSO-only control, but there was no significant increase when curdlan was co-applied with 25 µg ml-1 cordycepin dissolved in DMSO. Injection of cordycepin into larvae of Galleria mellonella (Lepidoptera: Pyralidae) resulted in dose-dependent mortality (LC50 of cordycepin = 2.1 mg per insect 6 days after treatment). Incubating conidia of C. militaris and Beauveria bassiana (Hypocreales, Cordycipitaceae; an EPF that does not synthesize cordycepin) with 3.0 mg ml-1 cordycepin had no effect on the numbers of conidia germinating in vitro. Co-injection of G. mellonella with a low concentration of cordycepin (3.0 mg ml-1) plus 10 or 100 conidia per insect of C. militaris or B. bassiana caused a significant decrease in insect median survival time compared to injection with the EPF on their own. Analysis of predicted vs. observed mortalities indicated a synergistic interaction between cordycepin and the EPF. The injection of C. militaris and B. bassiana into G. mellonella resulted in increased expression of the insect immune effector genes lysozyme, IMPI and gallerimycin at 72 h post injection, but this did not occur when the EPF were co-injected with 3.0 mg ml-1 cordycepin. In addition, we observed increased expression of IMPI and lysozyme at 48 h after injection with C. militaris, B. bassiana and sham injection (indicating a wounding response), but this was also prevented by application of cordycepin. These results suggest that cordycepin has potential to act as a suppressor of the immune response during fungal infection of insect hosts.

Project description:Cordycepin, an important active substance in Cordyceps militaris, possesses antiviral and other beneficial activities. In addition, it has been reported to effectively promote the comprehensive treatment of COVID-19 and thus has become a research hotspot. The addition of naphthalene acetic acid (NAA) is known to significantly improve the yield of cordycepin; however, its related molecular mechanism remains unclear. We conducted a preliminary study on C. militaris with different concentrations of NAA. We found that treatment with different concentrations of NAA inhibited the growth of C. militaris, and an increase in its concentration significantly improved the cordycepin content. In addition, we conducted a transcriptome and metabolomics association analysis on C. militaris treated with NAA to understand the relevant metabolic pathway of cordycepin synthesis under NAA treatment and elucidate the relevant regulatory network of cordycepin synthesis. Weighted gene co-expression network analysis (WGCNA), transcriptome, and metabolome association analysis revealed that genes and metabolites encoding cordycepin synthesis in the purine metabolic pathway varied significantly with the concentration of NAA. Finally, we proposed a metabolic pathway by analyzing the relationship between gene-gene and gene-metabolite regulatory networks, including the interaction of cordycepin synthesis key genes; key metabolites; purine metabolism; TCA cycle; pentose phosphate pathway; alanine, aspartate, and glutamate metabolism; and histidine metabolism. In addition, we found the ABC transporter pathway to be significantly enriched. The ABC transporters are known to transport numerous amino acids, such as L-glutamate, and participate in the amino acid metabolism that affects the synthesis of cordycepin. Altogether, multiple channels work together to double the cordycepin yield, thereby providing an important reference for the molecular network relationship between the transcription and metabolism of cordycepin synthesis.

Dataset Information

Transcriptome Analysis Reveals the Flexibility of Cordycepin Network in Cordyceps militaris Activated by L-Alanine Addition.

Publications

Transcriptome Analysis Reveals the Flexibility of Cordycepin Network in <i>Cordyceps militaris</i> Activated by L-Alanine Addition.

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