Efg1 Controls caspofungin-induced cell aggregation of Candida albicans through the adhesin Als1.
Echinocandin drugs such as caspofungin (CASP), micafungin, and anidulafungin inhibit fungal cell wall biogenesis by blocking Fks1-mediated β-glucan deposition into the cell surface. Candins have become suitable drugs to treat life-threatening diseases caused by several fungal species, including Candida albicans, that are pathogenic for humans. Here, we present the discovery of a novel CASP-induced flocculation phenotype of C. albicans, which formed large cell aggregates in the presence of CASP. High concentrations of sugars such as mannose or glucose inhibit CASP-induced flocculation and improve survival of C. albicans cells exposed to CASP. Notably, exposure of C. albicans cells to CASP triggers Efg1-dependent expression of the adhesin ALS1 and induces invasive growth on agar plates. Indeed, cells lacking either Efg1 or Als1 show strongly diminished CASP-induced flocculation, and the absence of Efg1 leads to marked CASP hypersensitivity. On the other hand, CASP-induced invasive growth is enhanced in cells lacking Efg1. Hence, CASP stress drives an Efg1-dependent response, indicating that this multifunctional transcriptional regulator, which is otherwise involved in filamentation, white-to-opaque switching, and virulence, also modulates cell wall remodeling upon CASP challenge. Taken together, our data suggest that CASP-induced cell wall damage activates Efg1 in parallel with the known cell integrity stress signaling pathway to coordinate cell wall remodeling.
Medical University Vienna, Christian Doppler Laboratory Infection Biology, Max F. Perutz Laboratories, Vienna, Austria.
Christa
C
Gregori
Walter
W
Glaser
Ingrid E
IE
Frohner
Cristina
C
Reinoso-Martín
Steffen
S
Rupp
Christoph
C
Schüller
Karl
K
Kuchler
D000935:Antifungal Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D000077336:Caspofungin; D002448:Cell Adhesion / Q000187:drug effects; D002473:Cell Wall / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D025141:Drug Resistance, Fungal / Q000235:genetics; D054714:Echinocandins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005427:Flocculation / Q000187:drug effects; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D055666:Lipopeptides; D008358:Mannose / Q000494:pharmacology; D050296:Microbial Viability / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
C093538:ALS1 protein, Candida albicans; D000935:Antifungal Agents; D004268:DNA-Binding Proteins; C121438:EFG1 protein, Candida albicans; D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C092603:MKC1 protein, Candida albicans; D020928:Mitogen-Activated Protein Kinases; D000077336:Caspofungin; D005947:Glucose; D008358:Mannose