Glycolysis-dependent sulfur metabolism orchestrates morphological plasticity and virulence in fungi

Fungi exhibit remarkable morphological plasticity, which allows them to undergo reversible transitions between distinct cellular states in response to changes in their environment. This phenomenon, termed fungal morphogenesis, is critical for fungi to survive and colonize diverse ecological niches and establish infections in a variety of hosts. Despite significant advancements in the field with respect to understanding the gene regulatory networks that control these transitions, the metabolic determinants of fungal morphogenesis remain poorly characterized. In this study, we uncover a previously uncharacterized, conserved dependency between central carbon metabolism and de novo biosynthesis of sulfur-containing amino acids that is critical for fungal morphogenesis, in two key fungal species. Using a multidisciplinary approach, we demonstrate that glycolytic flux is crucial to drive fungal morphogenesis in a cAMP-independent manner and perturbation of this pathway leads to a significant downregulation in the expression of genes involved in de novo biosynthesis of sulfur-containing amino acids. Remarkably, exogenous supplementation of sulfur-containing amino acids robustly rescues the morphogenesis defect induced by the perturbation of glycolysis in both Saccharomyces cerevisiae and Candida albicans, underscoring the pivotal role of de novo biosynthesis of sulfur-containing amino acid as a downstream effector of morphogenesis. Furthermore, a C. albicans mutant lacking the glycolytic enzyme, phosphofructokinase-1 (Pfk1) exhibited significantly reduced survival within murine macrophages and attenuated virulence in a murine model of systemic candidiasis. Overall, our work elucidates a previously uncharacterized coupling between glycolysis and sulfur metabolism that is critical for driving fungal morphogenesis, contributing to our understanding of this conserved phenomenon.

• Publication year

  2025

• Venue

  bioRxiv

• Publication date

  2025-11-21

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.7554/eLife.109075PMID 41649875PMCID 12880806
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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  2018influential reference
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  2016cited by this paper
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• and infectious disease

  2015cited by this paper
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• Conflict of interest.

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• G-protein coupled receptor from yeast Saccharomyces cerevisiae.

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• Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS.

  1992influential reference
• A View of Fungal Ecology

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• High efficiency transformation of intact yeast cells using single stranded nucleic acids as a carrier

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