title: Candida albicans Cek1 mitogen-activated protein kinase signaling enhances fungicidal activity of salivary histatin 5.
abstract: Candida albicans is a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC. C. albicans senses its environment by mitogen-activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either by N-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility of C. albicans cells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility in C. albicans.
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, New York, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, New York, USA.
authors.forename: Sumant
authors.initials: S
authors.lastname: Puri
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, New York, USA.
authors.forename: Swetha
authors.initials: S
authors.lastname: Tati
authors.affiliation: Department of Biological Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Cullen
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, New York, USA edgerto@buffalo.edu.
authors.forename: Mira
authors.initials: M
authors.lastname: Edgerton
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D054808:Histatins / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012463:Saliva / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D054808:Histatins; C077339:CEK1 protein, Candida albicans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases
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