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

Müller R, König A, Groth S, Zarnowski R, Visser C, Handrianz T, Maufrais C, Krüger T, Himmel M, Lee S, Priest EL, Yildirim D, Richardson JP, Blango MG, Bougnoux ME, Kniemeyer O, d'Enfert C, Brakhage AA, Andes DR, Trümper V, Nehls C, Kasper L, Mogavero S, Gutsmann T, Naglik JR, Allert S, Hube B (2024) Secretion of the fungal toxin candidalysin is dependent on conserved precursor peptide sequences. Nat Microbiol 9(3), 669-683.

Abstract

The opportunistic fungal pathogen Candida albicans damages host cells via its peptide toxin, candidalysin. Before secretion, candidalysin is embedded in a precursor protein, Ece1, which consists of a signal peptide, the precursor of candidalysin and seven non-candidalysin Ece1 peptides (NCEPs), and is found to be conserved in clinical isolates. Here we show that the Ece1 polyprotein does not resemble the usual precursor structure of peptide toxins. C. albicans cells are not susceptible to their own toxin, and single NCEPs adjacent to candidalysin are sufficient to prevent host cell toxicity. Using a series of Ece1 mutants, mass spectrometry and anti-candidalysin nanobodies, we show that NCEPs play a role in intracellular Ece1 folding and candidalysin secretion. Removal of single NCEPs or modifications of peptide sequences cause an unfolded protein response (UPR), which in turn inhibits hypha formation and pathogenicity in vitro. Our data indicate that the Ece1 precursor is not required to block premature pore-forming toxicity, but rather to prevent intracellular auto-aggregation of candidalysin sequences.

Leibniz-HKI-Authors

Stefanie Allert
Matthew Blango
Axel A. Brakhage
Maximilian Himmel
Bernhard Hube
Lydia Kasper
Olaf Kniemeyer
Annika König
Thomas Krüger
Selene Mogavero
Rita Müller
Verena Trümper
Corissa Visser
Deniz Yildirim

Awards

DGHM-Paper of the Month March 2024

Identifier

doi: 10.1038/s41564-024-01606-z

PMID: 38388771