Elucidating the role of Candida albicans Ece1 peptides
Final Report Abstract
One of the key virulence attributes of the human pathogenic fungus Candida albicans is its ability to undergo a morphological yeast-to-hypha transition accompanied by the expression of distinct hyphal associated genes, including ECE1, encoding the peptide toxin candidalysin. The precursor of this toxin is embedded in a pre-pro-protein consisting of a signal peptide and seven short additional non-candidalysin Ece1 peptides (NCEPs). While several studies have shown that candidalysin is critical for driving mucosal and systemic infections, the functional roles of NCEPs remain unknown. In this study, we explored three different possible principle functions for NCEPs: (1) a role in fungal biology, (2) a role in modulating candidalysin function, and/or (3) a role as host effector peptides. While we could not find evidence for a role of NCEPs as host effector peptides, our data strongly suggest that NCEPs play a fundamental role in C. albicans biology by preventing auto-aggregation of candidalysin sequences, thereby ensuring proper Ece1 folding, processing, normal hyphal growth, and efficient candidalysin secretion. This function is connected with a role in modulating candidalysin function as the association of candidalysin with NCEPs goes potentially beyond the secretory pathway and remains in the extracellular space to avoid auto-aggregation. The evolutionary conservation of the defined Ece1 structure must be associated with a high selective pressure and thus indicates the fundamental importance of candidalysin for the lifestyle of C. albicans and may explain why this fungus is the most successful pathogenic Candida species.
Publications
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Fungal factors involved in host immune evasion, modulation and exploitation during infection. Cellular Microbiology, 23(1).
König, Annika; Müller, Rita; Mogavero, Selene & Hube, Bernhard
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Candidalysins Are a New Family of Cytolytic Fungal Peptide Toxins. mBio, 13(1).
Richardson, Jonathan P.; Brown, Rhys; Kichik, Nessim; Lee, Sejeong; Priest, Emily; Mogavero, Selene; Maufrais, Corinne; Wickramasinghe, Don N.; Tsavou, Antzela; Kotowicz, Natalia K.; Hepworth, Olivia W.; Gallego-Cortés, Ana; Ponde, Nicole O.; Ho, Jemima; Moyes, David L.; Wilson, Duncan; D.’Enfert, Christophe; Hube, Bernhard & Naglik, Julian R.
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Secretion of the fungal toxin candidalysin is dependent on conserved precursor peptide sequences. Nature Microbiology, 9(3), 669-683.
Müller, Rita; König, Annika; Groth, Sabrina; Zarnowski, Robert; Visser, Corissa; Handrianz, Tom; Maufrais, Corinne; Krüger, Thomas; Himmel, Maximilian; Lee, Sejeong; Priest, Emily L.; Yildirim, Deniz; Richardson, Jonathan P.; Blango, Matthew G.; Bougnoux, Marie-Elisabeth; Kniemeyer, Olaf; d.’Enfert, Christophe; Brakhage, Axel A.; Andes, David R. ... & Hube, Bernhard
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The hyphal-specific toxin candidalysin promotes fungal gut commensalism. Nature, 627(8004), 620-627.
Liang, Shen-Huan; Sircaik, Shabnam; Dainis, Joseph; Kakade, Pallavi; Penumutchu, Swathi; McDonough, Liam D.; Chen, Ying-Han; Frazer, Corey; Schille, Tim B.; Allert, Stefanie; Elshafee, Osama; Hänel, Maria; Mogavero, Selene; Vaishnava, Shipra; Cadwell, Ken; Belenky, Peter; Perez, J. Christian; Hube, Bernhard; Ene, Iuliana V. & Bennett, Richard J.
