Gl PRMT5 inhibits Gl PP2C1 via symmetric dimethylation and regulates the biosynthesis of secondary metabolites in Ganoderma lucidum

PRMT5, a type II arginine methyltransferase, is involved in transcriptional regulation, RNA processing and other biological processes and signal transduction. Secondary metabolites are vital pharmacological compounds in Ganoderma lucidum , and their content is an important indicator for evaluating the quality of G. lucidum . Here, we found that Gl PRMT5 negatively regulates the biosynthesis of secondary metabolites. In further in-depth research, Gl PP2C1 (a type 2C protein phosphatase) was identified out as an interacting protein of Gl PRMT5 by immunoprecipitation-mass spectrometry (IP-MS). Further mass spectrometry detection revealed that Gl PRMT5 symmetrically dimethylates the arginine 99 (R99) and arginine 493 (R493) residues of Gl PP2C1 to weaken its activity. The symmetrical dimethylation modification of the R99 residue is the key to affecting Gl PP2C1 activity. Symmetrical demethylation-modified Gl PP2C1 does not affect the interaction with Gl PRMT5. In addition, silencing GlPP2C1 clearly reduced GA content, indicating that Gl PP2C1 positively regulates the biosynthesis of secondary metabolites in G. lucidum . In summary, this study reveals the molecular mechanism by which Gl PRMT5 regulates secondary metabolites, and these studies provide further insights into the target proteins of Gl PRMT5 and symmetric dimethylation sites. Furthermore, these studies provide a basis for the mutual regulation between different epigenetic modifications.