Physiology and Pathogenicity of Stress
Sulfur metabolites are essential for many cellular processes including protein synthesis, methylation reactions,
control of redox balance and detoxification of xenobiotics.
Sulfur metabolites (methionine, cysteine, S-adenosylmethionine, glutathione…) are involved in several vital cellular processes, such as protein synthesis, methylation of macromolecules, or control of the redox balance. Our team is particularly interested in the survival mechanisms set up by the cell in case of deficiency of these sulfur compounds; with the yeast Saccharomyces cerevisiae as a model.
Sulfur metabolism (Fig. 1) is highly conserved throughout evolution. It occupies a special position in cellular function and homeostasis because of the reactivity of thiols and the characteristics of the two sulfur-containing amino acids, methionine and cysteine. In addition to their role in proteins, these amino acids are the precursors of two key cellular compounds: on the one hand, S-adenosylmethionine (SAM), which is the major donor of methyl groups for the methylation of nucleic acids, proteins and lipids; and on the other hand, glutathione (GSH), which is the most abundant antioxidant in cells.
Figure 1: Sulfur metabolism in S. cerevisiae.
It should be noted that the part allowing the assimilation of sulfate to lead to homocysteine does not exist in humans, but the other parts are well conserved.
Sulfur metabolism is finely regulated to meet cellular needs since the lack or excessive accumulation of certain sulfur compounds can have deleterious effects on cell physiology, aging or more generally on the health of organisms. Several levels of regulation have been described. For example, we have demonstrated in S. cerevisiae (i) tight transcriptional control involving five transcription factors and a ubiquitin ligase (Kuras and Thomas, 1995; Kuras et al 1996, 1997, 2002; Cormier et al 2010) (fig 2), (ii) a specific sulfur-sparing program designed to replace abundant enzymes with sulfur-containing amino acid-poor iso-forms (Fauchon et al 2002; Pereira et al 2008), (iii) a dynamic control of GSH degradation (Baudouin-Cornu et al 2012). Together, these regulations allow the maintenance of essential sulfur compound pools at a physiological level, independent of variations in sulfur sources and their availability in the cellular environment.
Figure 2: Regulation of sulfur metabolism genes in S cerevisiae
We have observed that yeast cells subjected to sulfur deficiency conditions stop dividing but remain viable for several weeks despite the essential nature of the sulfur compounds. Moreover, we have shown that sulfur deficiency triggers a profound remodeling of the transcriptome very quickly. The question is to know to what extent and how this rapid change in the gene expression program can ultimately ensure cell survival over time. The objective of our current work is to answer this question by deciphering, at the cellular and molecular levels, the mechanisms involved in maintaining cell viability during prolonged sulfur nutrient deficiency.
More generally, these studies aim to deepen our understanding of the consequences of nutritional stress on cell function and behavior. In the longer term, we hope that the results will contribute to the identification of new therapeutic targets in the fight against cancers and diseases of aging.
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