Research in our group is focused on two major topics: 1) the molecular genetics and biochemistry of nutrient sensing and signaling in yeast (Saccharomyces cerevisiae), and 2) the development of novel genetic technologies and their application for the generation of superior industrial yeast strains
1. The molecular genetics and biochemistry of nutrient sensing and signaling in yeast (Saccharomyces cerevisiae)
Nutrients not only serve as substrates for production of energy and building blocks, but also exert dramatic regulatory effects on cells. Although several signaling pathways triggered by specific nutrients have been elucidated in great detail, much less is known how different nutrients can act together on a single pathway to control cellular processes such as cell growth and fermentation rate. Yeast provides a powerful molecular-genetic model system for studying the complex mechanisms underlying cellular processes controlled by multiple nutrients.
Our research has resulted in elucidation of the glucose-sensing network that controls the cAMP - Protein Kinase A (PKA) pathway in yeast. This pathway affects many important cellular targets, including storage compound levels, stress tolerance and responses, growth and fermentation rate, gene expression, developmental processes, etc. The cAMP - PKA pathway also plays an important role in mammalian cells as signal transmitter for the action of hormones and other environmental signals. Glucose is sensed by two systems that act in concert: a G-protein coupled receptor system that senses extracellular glucose and a system activated by glycolytic flux that activates the Ras proteins. Elucidation of this glucose-sensing system has also resulted in the discovery of an adenylate cyclase bypass pathway that directly connects the Galpha protein to PKA. Since part of the glucose-sensing network involves glucose activation of the Ras proteins, this research has high relevance for understanding the connection between the high fermentative glycolytic flux of cancer cells and their unbridled cellular proliferation.
The PKA pathway in yeast is also controlled by all other essential nutrients in addition to the control by glucose: nitrogen sources (amino acids and ammonium), phosphate, sulfate and probably micronutrients as well. A major outcome of the research on the mechanisms by which the other nutrients affect the PKA pathway has been the discovery of nutrient transceptors: proteins that combine the functions of transporter and receptor. This research has led to the discovery of nutrient analogues that cannot be transported by the transceptors but can act as signaling agonists to activate their receptor function. Current work focusses on the signaling pathway activated by the transceptors and on the connection between transceptor signaling and nutrient-induced internalization of the transceptors by ubiquitination and endocytosis.
2. The development of novel genetic technologies and their application for the generation of superior industrial yeast strains
Our group has developed pooled-segregant whole-genome sequence analysis for polygenic analysis of complex yeast traits with commercial importance: ethanol tolerance, maximal ethanol accumulation capacity, thermotolerance, low glycerol/high ethanol ratio, acetic acid tolerance, flavour compound production, etc. The superior alleles identified in this way in natural yeast strains with superior properties are used for the targeted improvement of industrial yeast strains by 'natural self cloning'. Other technologies for polygenic analysis of complex traits and for targeted improvement of industrial yeast strains are also under development. These technologies are used for the development of yeast strains for bioethanol production, beer brewing, wine production, bakery applications, production of biochemicals, etc.
Our group has also developed industrial yeast strains for cellulosic bioethanol production that combine efficient xylose fermentation with high inhibitor tolerance. These strains have shown high performance in lignocellulose hydrolysates derived from different cellulosic waste materials and bioenergy crops. These superior strains are currently further improved to boost their stress tolerance and versatility for use with many different types of hydrolysates.
Our group also uses yeast as a tool to study mammalian genes with medical importance, such as genes involved in neurodegenerative diseases.