Homeostasis of aggregation-prone metabolites: the possible role of Atr1 in adenine transport in yeast

Adenine is one of the life-essential building blocks that compose DNA. Recent evidence from our lab proved that this ubiquitous molecule, as well as other nucleobases and amino acids, could self-assemble and form cytotoxic amyloid-like structures. These ‘metabolite amyloids’ show significant biophysical and chemical similarity to their proteinaceous counterparts, which have been associated with various human disorders including Alzheimer’s disease, Parkinson’s disease, and type II diabetes. While such metabolite nanostructures have been avidly studied in vitro, little is known about the biological consequences of metabolite self-assembly, as well as of the intracellular homeostatic mechanisms that keep aggregation-prone metabolites from aggregating. Aiming to tackle these fundamental questions, we have previously established a novel in vivo model for adenine accumulation and self-assembly in yeast by blocking the enzymatic pathway downstream to adenine. This manipulation lead to the formation of amyloid-like structures and severe growth inhibition upon adenine feeding. Here, we carried out a systematic genome-wide screen to identify genes that rescue the notable adenine-sensitivity of the salvage mutant upon overexpression. Using the Synthetic Genetic Array (SGA) methodology we identified ATR1, a gene encoding a membrane-bound transporter of the evolutionary-conserved major facilitator superfamily, as a strong suppressor of the growth phenotype. Interestingly, Atr1 was previously annotated as an efflux pump of aminotriazole, a synthetic toxin which shows notable chemical similarity to adenine. Our results suggest a new and crucial function of Atr1 as an adenine transporter and provide proof-of-concept for the essential role of quality-control mechanisms that maintain metabolite homeostasis.