Abstract
Discoveries on the toxic effects of cysteine accumulation and, particularly, recent findings on the many physiological roles of one of the products of cysteine catabolism, hydrogen sulfide (H2S), are highlighting the importance of this amino acid and sulfur metabolism in a range of cellular activities. It is also highlighting how little we know about this critical part of cellular metabolism. In the work described here, a genome-wide screen using a deletion collection of Saccharomyces cerevisiae revealed a surprising set of genes associated with this process. In addition, the yeast vacuole, not previously associated with cysteine catabolism, emerged as an important compartment for cysteine degradation. Most prominent among the vacuole-related mutants were those involved in vacuole acidification; we identified each of the eight subunits of a vacuole acidification sub-complex (V1 of the yeast V-ATPase) as essential for cysteine degradation. Other functions identified included translation, RNA processing, folate-derived one-carbon metabolism, and mitochondrial iron-sulfur homeostasis. This work identified for the first time cellular factors affecting the fundamental process of cysteine catabolism. Results obtained significantly contribute to the understanding of this process and may provide insight into the underlying cause of cysteine accumulation and H2S generation in eukaryotes.
Highlights
The concentration of free intracellular cysteine is tightly regulated in eukaryotic and prokaryotic cells, serving two opposing homeostatic requirements
In this paper we describe a genome-wide survey using a haploid EUROSCARF S. cerevisiae gene deletion library to shed light on the cellular processes influencing cysteine catabolism
While developing a novel high-throughput assay for H2S detection [22], we noted that S. cerevisiae laboratory strain BY4742 did not produce detectable concentrations of H2S when grown in a chemically defined medium
Summary
The concentration of free intracellular cysteine is tightly regulated in eukaryotic and prokaryotic cells, serving two opposing homeostatic requirements. Consistent with the evolutionary conservation of cysteine catabolism, mammalian CBS- and CSE-encoding genes are similar to those of yeast and bacteria [16,17,18,19]. Expression of the gene encoding a human CBS in yeast was able to recover cysteine-auxotrophy caused by deletion of the yeast native CBS [16]. The predicted yeast CSE product was found to be closely related to rat and E. coli CSE [19]. These similarities reinforce the utility of S. cerevisiae as a model eukaryotic system to explore cellular homeostasis of cysteine and the catabolism of cysteine to release H2S. In this paper we describe a genome-wide survey using a haploid EUROSCARF S. cerevisiae gene deletion library to shed light on the cellular processes influencing cysteine catabolism
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