G‐protein signalling mediates differential production of toxic secondary metabolites

Abstract

Filamentous fungi elaborate a complex array of secondary metabolites, including antibiotics and mycotoxins. As many of these compounds pose significant economic and health concerns, elucidation of the underlying cellular mechanisms that control their production is essential. Previous work revealed that synthesis of the carcinogenic mycotoxins sterigmatocystin (ST) and aflatoxin (AF) in Aspergillus species is negatively controlled by FadA, the α‐subunit of a heterotrimeric G‐protein. In sharp contrast, we show here that the dominant activating fadA allele, fadAG42R, stimulates transcription of a gene from the A. nidulans penicillin (PN) gene cluster and elevates penicillin production. Thus, FadA has opposite roles in regulating the biosynthesis of a potent antibiotic (PN) and a lethal mycotoxin (ST) in A. nidulans. Furthermore, expression of fadAG42R in Fusarium sporotrichioides increases trichothecene (TR) mycotoxin production and alters TR gene expression. Our findings reveal that a G‐protein defines an important control point for differential expression of fungal secondary metabolites within and across fungal genera. These data provide critical evidence suggesting that targeting G‐protein signal transduction pathways as a means of controlling or preventing the production of a single mycotoxin could have serious undesirable consequences with regard to the production of other secondary metabolites.

Relationship between Secondary Metabolism and Fungal Development

“…Inactivation of a G ␣-subunit, FadA, leads to concomitant sporulation and mycotoxin production. Some of the G-protein signaling regulatory elements described for A. nidulans are conserved among other filamentous fungi (6,16,55,62,66,115,116,129). However, they can have different or even opposite roles in regulating the biosynthesis of natural products (115).…”

“…A mutation in the Fusarium verticillioides FCC1 gene results in reduced sporulation and reduced fumonisin B 1 biosynthesis (104). Also, introducing a dominant-activated allele of an A. nidulans ␣ G-protein into Fusarium sporotrichioides produces strains with elevated production of T-2 mycotoxin but reduced conidium formation (115).…”

“…Deletion of this gene results in reduction of spore production and failure to synthesize antibiotics, without affecting growth. In A. nidulans, a relationship between conidiation and the production of the antibiotic penicillin has also recently been described (115). The dominant activating fadA G42R allele, which represses conidiation and sterigmatocystin biosynthesis, stimulates the expression of ipnA (an enzymatic gene of the A. nidulans penicillin gene cluster) and stimulates concomitant penicillin biosynthesis (115).…”

“…allele into the fungus F. sporotrichioides generated strains with reduced conidial production and increased trichothecene production (115). Expression of the fadA G42R allele reduced Fusarium spore production 50 to 95% and resulted in delayed radial growth compared with the wild type.…”

A Novel Regulatory Gene, Tri10 , Controls Trichothecene Toxin Production and Gene Expression

“…The regulation of trichothecene production is equally complex, and as with many secondary metabolites it can be controlled in liquid culture by the availability of certain nutrients, oxygen, pH, and temperature (33), as well as by the modulation of signal transduction pathways mediated by a G-protein G␣ subunit (31). However, the complete genetic nature of the induction and repression of trichothecene biosynthesis is just beginning to be understood.…”