Inducible expression of secondary metabolites using a synthetic transcription factor in an essentially background-free system

Fungal secondary metabolites (SM) are a highly diverse group of compounds with many different biological activities; many can be used for medicinal purposes. For their industrial production, mainly the native hosts are used, which can be problematic regarding cultivation conditions (expensive additives, induction of SM production). An approach to circumvent these problems is heterologous expression in fungi. We have constructed a novel synthetic transcription factor for the industrial workhorse Trichoderma reesei, which facilitates strong and tightly controllable gene expression of its target genes using the cheap inducer estradiol. T. reesei is industrially used to produce cellulases and hemicellulases with outstanding production rates. Recently, we have identified a pleiotropic regulator of the secondary metabolism (1). The over-expression of this transcription factors results in a reduction of the native SM production in this fungus which possess already only few SM-encoding genes. The major SM of T. reesei are sorbicillinoids, whose synthesis can be completely shut off by deleting their main regulator (2). Additionally, we have identified and established a set of loci for targeted gene insertions, which allow insertion of SM encoding genes, e.g. the genes for biosynthesis of the pharmaceutical Lovastatin. All these findings and innovations enable strong and inducible expression of SM without the production of any mentionable side-products.

1. Derntl C, Kluger B, Bueschl C, Schuhmacher R, Mach RL, Mach-Aigner AR. 2017. Transcription factor Xpp1 is a switch between primary and secondary fungal metabolism. Proc Natl Acad Sci U S A 114:E560-E569.
2. Derntl C, Rassinger A, Srebotnik E, Mach RL, Mach-Aigner AR. 2016. Identification of the Main Regulator Responsible for Synthesis of the Typical Yellow Pigment Produced by Trichoderma reesei. Appl Environ Microbiol 82:6247-6257.