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Cwh8 moonlights as a farnesyl pyrophosphate phosphatase and is essential for farnesol biosynthesis in Candida albicans

Summary

Candida albicans is a common fungus that causes serious infections in people with weakened immune systems. The fungus produces a molecule called farnesol that prevents it from growing in long filaments, which are associated with virulence. Researchers discovered that an enzyme called Cwh8 is absolutely essential for making farnesol, and when this enzyme is missing, the fungus becomes highly sensitive to the antifungal drug fluconazole, suggesting a potential strategy to overcome drug resistance.

Background

Candida albicans is an opportunistic pathogen that switches between yeast and filamentous morphologies in response to environmental factors, with hyphal growth associated with virulence. Farnesol, a secreted autoregulatory molecule, represses this filamentation and is derived from farnesyl pyrophosphate (FPP) in the ergosterol biosynthesis pathway. Despite 20 years of research, the precise mechanisms for farnesol synthesis remain poorly understood.

Objective

To identify genes essential for farnesol biosynthesis in C. albicans, since known FPP phosphatases Dpp1, Dpp2, and Dpp3 account for only a modest reduction in farnesol production. The study employed transcription factor mutants with altered farnesol production combined with transcriptomic analysis to identify novel genes involved in this pathway.

Results

CWH8 was identified as the only transcript correlated with farnesol production across multiple transcription factor mutants. cwh8ΔΔ mutants showed >99% reduction in farnesol compared to parent strain and had ~900-fold lower levels of farnesyl phosphate. Complementation with C. albicans CWH8 restored farnesol production, but complementation with CWH8 from non-farnesol-secreting Clavispora lusitaniae restored cell wall integrity but not farnesol production.

Conclusion

Cwh8, previously known as a dolichyl pyrophosphate phosphatase, is essential for farnesol biosynthesis in C. albicans by converting FPP to FP. The finding that species-specific differences in Cwh8 substrate specificity or cofactor interactions underlie farnesol secretion suggests how extracellular signaling systems can evolve. cwh8ΔΔ mutants demonstrated fungicidal rather than fungistatic responses to fluconazole, linking farnesol production to antifungal drug resistance.
  • Published in:mBio,
  • Study Type:Experimental Research,
  • Source: 40919816
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