Multiple Transceptors for Macro- and Micro-Nutrients Control Diverse Cellular Properties Through the PKA Pathway in Yeast: A Paradigm for the Rapidly Expanding World of Eukaryotic Nutrient Transceptors Up to Those in Human Cells

Abstract

The nutrient composition of the medium has dramatic effects on many cellular properties in the yeast Saccharomyces cerevisiae. In addition to the well-known specific responses to starvation for an essential nutrient, like nitrogen or phosphate, the presence of fermentable sugar or a respirative carbon source leads to predominance of fermentation or respiration, respectively. Fermenting and respiring cells also show strong differences in other properties, like storage carbohydrate levels, general stress tolerance and cellular growth rate. However, the main glucose repression pathway, which controls the switch between respiration and fermentation, is not involved in control of these properties. They are controlled by the protein kinase A (PKA) pathway. Addition of glucose to respiring yeast cells triggers cAMP synthesis, activation of PKA and rapid modification of its targets, like storage carbohydrate levels, general stress tolerance and growth rate. However, starvation of fermenting cells in a glucose medium for any essential macro- or micro-nutrient counteracts this effect, leading to downregulation of PKA and its targets concomitant with growth arrest and entrance into G0. Re-addition of the lacking nutrient triggers rapid activation of the PKA pathway, without involvement of cAMP as second messenger. Investigation of the sensing mechanism has revealed that the specific high-affinity nutrient transporter(s) induced during starvation function as transporter-receptors or transceptors for rapid activation of PKA upon re-addition of the missing substrate. In this way, transceptors have been identified for amino acids, ammonium, phosphate, sulfate, iron, and zinc. We propose a hypothesis for regulation of PKA activity by nutrient transceptors to serve as a conceptual framework for future experimentation. Many properties of transceptors appear to be similar to those of classical receptors and nutrient transceptors may constitute intermediate forms in the development of receptors from nutrient transporters during evolution. The nutrient-sensing transceptor system in yeast for activation of the PKA pathway has served as a paradigm for similar studies on candidate nutrient transceptors in other eukaryotes and we succinctly discuss the many examples of transceptors that have already been documented in other yeast species, filamentous fungi, plants, and animals, including the examples in human cells.

Yeast filamentation signaling is connected to a specific substrate translocation mechanism of the Mep2 transceptor

“…In 1998, Lorenz and Heitman proposed, for the first time to our knowledge, that a yeast transporter, Mep2, could play an additional sensor role triggering filamentation signaling [20]. Nowadays, the concept of transceptors, used to define proteins combining a substrate transport capacity and a substrate receptor function coupled to a signal transmission, appears to concern transporters of all kind of micro-and macro-nutrients in eukaryotes, from fungi to human [64,65]. Albeit an exciting concept, the firm demonstration of the existence of transceptors with separated transport and sensing functions remains highly challenging.…”

Construction of industrial baker’s yeast with high level of cAMP

“…The regulatory and catalytic subunits of PKA were encoded by the gene of BCY1 and TPKs, respectively, and regulated the intracellular accumulation of cAMP in yeast S. cerevisiae cell. And PKA was essential for yeast cell survival, its activity abolishment was lethal for yeast strain (Steyfkens, Zhang, Van Zeebroeck, & Thevelein, ). Therefore, PKA activity was weakened through the TPK2 promoter truncation and the deletion of BCY1 , TPK1, and TPK3 to enhance the intracellular cAMP levels in industrial yeast strain without influence to yeast fermentation.…”

“…The regulatory and catalytic subunits of PKA were encoded by the gene of BCY1 and TPKs, respectively, and regulated the intracellular accumulation of cAMP in yeast S. cerevisiae cell. And PKA was essential for yeast cell survival, its activity abolishment was lethal for yeast strain (Steyfkens, Zhang, Van Zeebroeck, & Thevelein, 2018).…”

Plant-Derived Antioxidants Protect the Nervous System From Aging by Inhibiting Oxidative Stress

“…When ingested by humans, plant proteins are hydrolyzed by the digestive system and many small peptides and amino acids are obtained. These amino acids often activate PKA while glutamate transporters of neurons and astrocytes can promote the cascade of the MAPK reaction (Steyfkens et al, 2018). There are a wide variety of active peptides that include antioxidant peptides and opioid peptides that have important neuroprotective effects.…”