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The very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase Phs1 regulates ATP levels and virulence in Cryptococcus neoformans

Summary

Researchers found that a protein called Phs1, which helps Cryptococcus neoformans (a dangerous fungus) produce essential fatty acids, is important for the fungus to cause disease. When this protein was removed, the fungus produced less melanin (a pigment), couldn’t grow well at body temperature, and had a weaker cell wall. Most importantly, the fungus produced less energy (ATP) and was much less deadly in infected mice, suggesting that blocking Phs1 could potentially be a new way to treat cryptococcal infections.

Background

Cryptococcus neoformans is a significant fungal pathogen causing life-threatening meningoencephalitis in immunocompromised individuals, particularly those with HIV/AIDS. Very-long-chain fatty acids (VLCFAs) are vital precursors for sphingolipid synthesis and cellular functions, with the enzyme Phs1 catalyzing a critical step in VLCFA synthesis.

Objective

This study investigated the role of the very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase Phs1 in regulating virulence factors, ATP levels, and cellular metabolism in Cryptococcus neoformans using transcriptomic and metabolomic analyses.

Results

The phs1Δ mutant exhibited significantly impaired melanin production, reduced growth at 39°C, compromised cell wall integrity, and substantially diminished virulence in mice. RNA-Seq revealed downregulation of 540 genes associated with ATP-dependent activities, while metabolomics showed disruptions in oxidative phosphorylation and the TCA cycle, with decreased ATP levels in knockout cells.

Conclusion

Phs1 plays a critical role in regulating virulence in C. neoformans through its effects on melanin production, thermotolerance, cell wall integrity, and cellular energy metabolism. The study highlights the importance of very-long-chain fatty acid metabolism and mitochondrial function in fungal pathogenesis.
  • Published in:BMC Microbiology,
  • Study Type:Experimental Study,
  • Source: PMID: 41299221, DOI: 10.1186/s12866-025-04518-y
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