A balancing act: How SmCSN5 fine-tunes medicinal compound biosynthesis in red sage
image: A hypothetical working model explaining the SmCSN5-SmMYB36-based regulation of tanshinone and phenolic acid biosynthesis. SmCSN5 interacted with SmMYB36 in the nucleus to promote the stability of SmMYB36 and enhance its ability to regulate the transcription of the target genes. MeJA promoted the expression of SmCSN5, thereby strengthening the capacity of SmMYB36 to regulate the transcription of the target genes, which led to a further improvement in tanshinone accumulation but a reduction in phenolic acid accumulation. Image link: https://academic.oup.com/view-large/figure/507964721/uhaf005f8.tif?login=false
Credit: Horticulture Research
Salvia miltiorrhiza, also known as red sage or Danshen, produces two major classes of bioactive metabolites—lipid-soluble tanshinones and water-soluble phenolic acids—widely used to treat cardiovascular and inflammatory diseases. However, the natural content of these compounds is often low and variable, influenced by environmental and genetic factors. Although many transcription factors have been linked to the regulation of these pathways, the mechanisms governing their stability and post-translational modification remain poorly understood. Due to these challenges, it is essential to explore how key regulators interact at the protein level to coordinate the synthesis of tanshinones and phenolic acids.
Researchers from Northwest A&F University, Yunnan Agricultural University, and Northeast Forestry University have reported a breakthrough in understanding the molecular regulation of Salvia miltiorrhiza’s secondary metabolism. Their study (DOI: 10.1093/hr/uhaf005), published on April 1, 2025, in Horticulture Research, reveals how the protein SmCSN5 interacts with the transcription factor SmMYB36 to fine-tune the biosynthesis of tanshinones and phenolic acids. Through molecular, biochemical, and genetic analyses, the team demonstrated that SmCSN5 enhances the stability and nuclear localization of SmMYB36, offering new strategies to boost the medicinal value of this important herb.
The researchers discovered that SmMYB36, a transcription factor previously known to activate tanshinone biosynthesis and suppress phenolic acid formation, is regulated by protein degradation. Using yeast two-hybrid, BiFC, CoIP, and pull-down assays, they confirmed that SmCSN5 physically interacts with SmMYB36, preventing its ubiquitin-mediated degradation. Overexpression of SmCSN5 in hairy roots of S. miltiorrhiza led to a marked increase in tanshinone content—such as cryptotanshinone and tanshinone IIA—while the levels of rosmarinic and salvianolic acids decreased. Conversely, silencing SmCSN5 reduced tanshinone accumulation and enhanced phenolic acid production. The study further demonstrated that SmCSN5 relocates from the cytoplasm to the nucleus when bound to SmMYB36, strengthening its regulatory function. Under methyl jasmonate (MeJA) treatment, SmCSN5 expression surged, amplifying SmMYB36 activity and promoting tanshinone biosynthesis. The findings suggest that the SmCSN5–SmMYB36 module acts as a molecular switch, coordinating post-translational regulation to balance the metabolic flux between two competing biosynthetic pathways.
"Our results highlight a novel layer of regulation in Salvia miltiorrhiza secondary metabolism," said Dr. Pengda Ma, corresponding author of the study. "SmCSN5 acts as a stabilizing cofactor that protects SmMYB36 from degradation, thereby promoting tanshinone accumulation while reducing phenolic acid synthesis. This interaction reveals how plants orchestrate complex metabolic decisions at the protein level. Such knowledge will help us design genetic strategies to improve the yield of pharmacologically important compounds in medicinal crops."
This discovery sheds light on how protein stability modulates the metabolic balance between tanshinones and phenolic acids, two crucial ingredients in cardiovascular therapeutics derived from Danshen. The SmCSN5–SmMYB36 interaction provides a powerful molecular target for metabolic engineering and synthetic biology, enabling selective enhancement of tanshinone production without compromising plant growth. Moreover, the study establishes a framework for investigating COP9 signalosome-mediated post-translational regulation in other medicinal plants. By harnessing these insights, researchers can develop Salvia miltiorrhiza varieties with optimized metabolite profiles and improved pharmacological efficiency.
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References
DOI
Original Source URL
https://doi.org/10.1093/hr/uhaf005
Funding information
This work was supported by the National Natural Science Foundation of China (Project No. 32270278) and Key project at central government level: the ability establishment of sustainable use for valuable Chinese medicine resources (2060302).
About Horticulture Research
Horticulture Research is an open access journal of Nanjing Agricultural University and ranked number one in the Horticulture category of the Journal Citation Reports ™ from Clarivate, 2024. The journal is committed to publishing original research articles, reviews, perspectives, comments, correspondence articles and letters to the editor related to all major horticultural plants and disciplines, including biotechnology, breeding, cellular and molecular biology, evolution, genetics, inter-species interactions, physiology, and the origination and domestication of crops.