Abstract
ABSTRACTCandida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. During mucosal infection, C. albicans undergoes a morphological transition from yeast to invasive filamentous hyphae that secrete candidalysin, a 31-amino-acid peptide toxin required for virulence. Candidalysin damages epithelial cell plasma membranes and stimulates the activating protein 1 (AP-1) transcription factor c-Fos (via p38–mitogen-activated protein kinase [MAPK]), and the MAPK phosphatase MKP1 (via extracellular signal-regulated kinases 1 and 2 [ERK1/2]–MAPK), which trigger and regulate proinflammatory cytokine responses, respectively. The candidalysin toxin resides as a discrete cryptic sequence within a larger 271-amino-acid parental preproprotein, Ece1p. Here, we demonstrate that kexin-like proteinases, but not secreted aspartyl proteinases, initiate a two-step posttranslational processing of Ece1p to produce candidalysin. Kex2p-mediated proteolysis of Ece1p after Arg61 and Arg93, but not after other processing sites within Ece1p, is required to generate immature candidalysin from Ece1p, followed by Kex1p-mediated removal of a carboxyl arginine residue to generate mature candidalysin. C. albicans strains harboring mutations of Arg61 and/or Arg93 did not secrete candidalysin, were unable to induce epithelial damage and inflammatory responses in vitro, and showed attenuated virulence in vivo in a murine model of oropharyngeal candidiasis. These observations identify enzymatic processing of C. albicans Ece1p by kexin-like proteinases as crucial steps required for candidalysin production and fungal pathogenicity.
Highlights
Candida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans
Candidalysin is an amphipathic 31-amino-acid cytolytic peptide toxin that is vitally important for C. albicans mucosal infection and functions by destabilizing the integrity of plasma membranes and activating epithelial immunity via the activating protein 1 (AP-1) transcription factor c-Fos, and the MAPK phosphatase MKP1 (3, 4)
The mutagenized constructs were introduced into a C. albicans ece1Δ/Δ null mutant (3) as the sole source of ECE1 to create a panel of alanine substitution mutants that allowed the importance of each Kex2p recognition site (KR) site in Ece1p to be interrogated individually and in combination
Summary
Candida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. C. albicans strains harboring mutations of Arg[61] and/or Arg[93] did not secrete candidalysin, were unable to induce epithelial damage and inflammatory responses in vitro, and showed attenuated virulence in vivo in a murine model of oropharyngeal candidiasis These observations identify enzymatic processing of C. albicans Ece1p by kexin-like proteinases as crucial steps required for candidalysin production and fungal pathogenicity. Candidalysin is an amphipathic 31-amino-acid (aa) cytolytic peptide toxin that is vitally important for C. albicans mucosal infection and functions by destabilizing the integrity of plasma membranes and activating epithelial immunity via the activating protein 1 (AP-1) transcription factor c-Fos (via the p38 –mitogen-activated protein kinase [MAPK] pathway), and the MAPK phosphatase MKP1 (via the extracellular signal-regulated kinase 1 and 2 [ERK1/2]–MAPK pathway) (3, 4). We hypothesized that the processing of Ece1p by Kex2p to generate candidalysin may be required for C. albicans pathogenicity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
