Identification of Ftr1 and Zrt1 as iron and zinc micronutrient transceptors for activation of the PKA pathway in Saccharomyces cerevisiae

Abstract

Multiple types of nutrient transceptors, membrane proteins that combine a transporter and receptor function, have now been established in a variety of organisms. However, so far all established transceptors utilize one of the macronutrients, glucose, amino acids, ammonium, nitrate, phosphate or sulfate, as substrate. This is also true for the Saccharomyces cerevisiae transceptors mediating activation of the PKA pathway upon re-addition of a macronutrient to glucose-repressed cells starved for that nutrient, re-establishing a fermentable growth medium. We now show that the yeast high-affinity iron transporter Ftr1 and high-affinity zinc transporter Zrt1 function as transceptors for the micronutrients iron and zinc. We show that replenishment of iron to iron-starved cells or zinc to zinc-starved cells triggers within 1-2 minutes a rapid surge in trehalase activity, a well-established PKA target. The activation with iron is dependent on Ftr1 and with zinc on Zrt1, and we show that it is independent of intracellular iron and zinc levels. Similar to the transceptors for macronutrients, Ftr1 and Zrt1 are strongly induced upon iron and zinc starvation, respectively, and they are rapidly downregulated by substrate-induced endocytosis. Our results suggest that transceptor-mediated signaling to the PKA pathway may occur in all cases where glucose-repressed yeast cells have been starved first for an essential nutrient, causing arrest of growth and low activity of the PKA pathway, and subsequently replenished with the lacking nutrient to re-establish a fermentable growth medium. The broadness of the phenomenon also makes it likely that nutrient transceptors use a common mechanism for signaling to the PKA pathway.

The SlZRT1 Gene Encodes a Plasma Membrane-Located ZIP (Zrt-, Irt-Like Protein) Transporter in the Ectomycorrhizal Fungus Suillus luteus

“…With our current data, we cannot conclude on a role for SlZRT1 as Zn receptor for signaling in order to adjust primary metabolism to external Zn availability. Such a role was reported recently for ScZRT1 ( Schothorst et al, 2017 ) and is certainly worth investigation in S. luteus and mycorrhizal fungi in general. Ectomycorrhizal fungi are well-known to offer their host plant a balanced nutrient supply by efficiently collecting limited nutrients and reducing the transfer of excess, potentially toxic elements.…”

“…These fluctuations in expression level could possibly reflect the cell’s Zn status. A similar expression pattern, though delayed in time was detected by Schothorst et al (2017) in S. cerevisiae for ScZRT1 in conditions of Zn deprivation. ScZRT1 transcripts peak at 2 days under Zn deprivation and decline again afterward.…”

“…Reciprocal BLASTp suggested the S. luteus protein with ID 22926, named SlZRT1 to be orthologous to the S. cerevisiae ScZRT1 transceptor. ScZRT1 functions as a high-affinity Zn uptake transporter and receptor ( Schothorst et al, 2017 ). Together with its homolog, the plasma membrane transporter ScZRT2, ScZRT1 is responsible for Zn uptake in Zn deficient yeast cells ( Gaither and Eide, 2001 ).…”

Identification of the Genetic Requirements for Zinc Tolerance and Toxicity inSaccharomyces cerevisiae

“…Hence, the activity of Zap1 is strongly enhanced in response to zinc limitation, inducing the expression of ZRT1 encoding a high-affinity zinc transporter while inhibiting the expression of ZRT2 encoding a low-affinity zinc transporter (Eide 2003;Wilson and Bird 2016). When espoused to high extracellular zinc concentrations, Zrt1 is removed from the plasma membrane rapidly by substrate-induced endocytosis (Schothorst et al 2017;Gitan and Eide 2000;Gitan et al 1998). The expression level of ZRT1 is induced over 100-fold in zinc-limited cells by Zap1, while ZRT2 is induced under mild zinc limitation but then inhibited by Zap1 in severe zinc limitation conditions (Zhao and Eide 1997;Bird et al 2004).…”

Evolutionary Engineering of an Iron-Resistant Saccharomyces cerevisiae Mutant and Its Physiological and Molecular Characterization

“…Pho84p also mediates rapid activation of the PKA (protein kinase A) pathway [56] similar to other transceptors that function both as a transporter and receptor. According to a recent study, the high-affinity iron transporter Ftr1p and high-affinity zinc transporter Zrt1p are also transceptors for the micronutrients iron and zinc in S. cerevisiae [57]. However, in M8FE, no gene expression changes were detected in ZRT1, while FTR1 was downregulated 2.16 times, as folds of the reference strain.…”