Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence
ABSTRACT Candida 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...
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American Society for Microbiology
2018
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oai:doaj.org-article:24e176a633bf41b5807b57f22b8e67012021-11-15T15:53:26ZProcessing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence10.1128/mBio.02178-172150-7511https://doaj.org/article/24e176a633bf41b5807b57f22b8e67012018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02178-17https://doaj.org/toc/2150-7511ABSTRACT Candida 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. IMPORTANCE Candida albicans is an opportunistic fungal pathogen that causes mucosal infection in millions of individuals worldwide. Successful infection requires the secretion of candidalysin, the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is derived from its parent protein Ece1p. Here, we identify two key amino acids within Ece1p vital for processing and production of candidalysin. Mutations of these residues render C. albicans incapable of causing epithelial damage and markedly reduce mucosal infection in vivo. Importantly, candidalysin production requires two individual enzymatic events. The first involves processing of Ece1p by Kex2p, yielding immature candidalysin, which is then further processed by Kex1p to produce the mature toxin. These observations identify important steps for C. albicans pathogenicity at mucosal surfaces.Jonathan P. RichardsonSelene MogaveroDavid L. MoyesMariana BlagojevicThomas KrügerAkash H. VermaBianca M. ColemanJacinto De La Cruz DiazDaniela SchulzNicole O. PondeGiulia CarranoOlaf KniemeyerDuncan WilsonOliver BaderSimona I. EnoiuJemima HoNessim KichikSarah L. GaffenBernhard HubeJulian R. NaglikAmerican Society for MicrobiologyarticleCandida albicanscandidalysinfungal infectionkexinmucosal immunityMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Candida albicans candidalysin fungal infection kexin mucosal immunity Microbiology QR1-502 |
| spellingShingle |
Candida albicans candidalysin fungal infection kexin mucosal immunity Microbiology QR1-502 Jonathan P. Richardson Selene Mogavero David L. Moyes Mariana Blagojevic Thomas Krüger Akash H. Verma Bianca M. Coleman Jacinto De La Cruz Diaz 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 Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| description |
ABSTRACT Candida 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. IMPORTANCE Candida albicans is an opportunistic fungal pathogen that causes mucosal infection in millions of individuals worldwide. Successful infection requires the secretion of candidalysin, the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is derived from its parent protein Ece1p. Here, we identify two key amino acids within Ece1p vital for processing and production of candidalysin. Mutations of these residues render C. albicans incapable of causing epithelial damage and markedly reduce mucosal infection in vivo. Importantly, candidalysin production requires two individual enzymatic events. The first involves processing of Ece1p by Kex2p, yielding immature candidalysin, which is then further processed by Kex1p to produce the mature toxin. These observations identify important steps for C. albicans pathogenicity at mucosal surfaces. |
| format |
article |
| author |
Jonathan P. Richardson Selene Mogavero David L. Moyes Mariana Blagojevic Thomas Krüger Akash H. Verma Bianca M. Coleman Jacinto De La Cruz Diaz 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 |
| author_facet |
Jonathan P. Richardson Selene Mogavero David L. Moyes Mariana Blagojevic Thomas Krüger Akash H. Verma Bianca M. Coleman Jacinto De La Cruz Diaz 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 |
| author_sort |
Jonathan P. Richardson |
| title |
Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| title_short |
Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| title_full |
Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| title_fullStr |
Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| title_full_unstemmed |
Processing of <italic toggle="yes">Candida albicans</italic> Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence |
| title_sort |
processing of <italic toggle="yes">candida albicans</italic> ece1p is critical for candidalysin maturation and fungal virulence |
| publisher |
American Society for Microbiology |
| publishDate |
2018 |
| url |
https://doaj.org/article/24e176a633bf41b5807b57f22b8e6701 |
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