Processing of Candida albicans Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence

• DOI: 10.1128/mbio.02178-17
• Publication Date: 2018-01-22T13:23:48Z
• Authors: Jonathan P. Richa...; Selene Mogavero; David L. Moyes; Mariana Blagojevic; Thomas Krüger; Akash H. Verma; Bianca M. Coleman; Jacinto De La Cru...; Daniela Schulz; Nicole O. Ponde; Giulia Carrano; Olaf Kniemeyer; Duncan Wilson; Oliver Bader; Simona I. Enoiu; Jemima Ho; Nessim Kichik; Sarah L. Gaffen; Bernhard Hube; Julian R. Naglik
• Keywords: Secretory protein; Virulence factor; Fungal protein

Candida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. During mucosal infection, C. undergoes a morphological transition from yeast to invasive filamentous hyphae that secrete candidalysin, 31-amino-acid peptide toxin required virulence. Candidalysin damages epithelial cell plasma membranes stimulates the activating protein 1 (AP-1) transcription factor c-Fos (via p38-mitogen-activated kinase [MAPK]), MAPK phosphatase MKP1 extracellular signal-regulated kinases 2 [ERK1/2]-MAPK), which trigger regulate proinflammatory cytokine responses, respectively. The candidalysin resides as discrete cryptic sequence within larger 271-amino-acid parental preproprotein, Ece1p. Here, we demonstrate kexin-like proteinases, but not secreted aspartyl initiate two-step posttranslational processing of Ece1p produce candidalysin. Kex2p-mediated proteolysis after Arg61 Arg93, other sites Ece1p, generate immature followed by Kex1p-mediated removal carboxyl arginine residue mature strains harboring mutations and/or Arg93 did were unable induce damage inflammatory responses vitro, showed attenuated virulence vivo murine model oropharyngeal candidiasis. These observations identify enzymatic proteinases crucial steps production pathogenicity.IMPORTANCECandida causes infection millions individuals worldwide. Successful requires secretion first cytolytic identified any human pathogen. derived its parent two key amino acids vital Mutations these residues render incapable causing markedly reduce Importantly, individual events. involves Kex2p, yielding then further processed Kex1p toxin. important pathogenicity at surfaces.