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Secretion of the fungal toxin candidalysin is dependent on conserved precursor peptide sequences

Rita Müller1, Annika König1,2, Sabrina Groth3

  • 1Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute (HKI), Jena, Germany.

Nature Microbiology
|February 22, 2024
PubMed

Insights

The Ece1 precursor protein in Candida albicans prevents self-toxicity by blocking candidalysin auto-aggregation. Non-candidalysin Ece1 peptides are crucial for proper folding and secretion of this fungal toxin.

Area of Science:

  • Mycology
  • Molecular Biology
  • Pathogenesis

Background:

  • Candida albicans is an opportunistic fungal pathogen that causes host cell damage using the peptide toxin candidalysin.
  • Candidalysin is secreted from the fungus via a precursor protein, Ece1, which contains non-candidalysin Ece1 peptides (NCEPs).
  • The Ece1 precursor structure and the role of NCEPs in candidalysin secretion are not fully understood.

Purpose of the Study:

  • To investigate the role of NCEPs within the Ece1 precursor protein in candidalysin folding, secretion, and toxicity.
  • To elucidate the mechanism by which the Ece1 precursor prevents self-toxicity.

Main Methods:

  • Construction and analysis of Ece1 mutants with deletions or modifications in NCEP sequences.
  • Mass spectrometry to analyze protein interactions and modifications.
  • Utilized anti-candidalysin nanobodies for detection and characterization.
  • Assessed the impact of mutations on the unfolded protein response (UPR), hypha formation, and pathogenicity in vitro.

Main Results:

  • The Ece1 polyprotein structure deviates from typical peptide toxin precursors.
  • Single NCEPs are sufficient to prevent host cell toxicity from candidalysin.
  • NCEPs are essential for correct intracellular Ece1 folding and subsequent candidalysin secretion.
  • Removal or modification of NCEPs triggers an unfolded protein response (UPR).
  • UPR induction leads to inhibition of hypha formation and reduced pathogenicity.

Conclusions:

  • The Ece1 precursor's primary role is not to prevent premature toxicity but to inhibit intracellular auto-aggregation of candidalysin.
  • NCEPs are critical for maintaining Ece1 protein homeostasis and regulating candidalysin secretion.
  • Disruption of NCEP function impacts C. albicans virulence by inducing UPR and impairing hyphal development.

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