AUTHOR=Milholland Kedric L. , AbdelKhalek Ahmed , Baker Kortany M. , Hoda Smriti , DeMarco Andrew G. , Naughton Noelle H. , Koeberlein Angela N. , Lorenz Gabrielle R. , Anandasothy Kartikan , Esperilla-Muñoz Antonio , Narayanan Sanjeev K. , Correa-Bordes Jaime , Briggs Scott D. , Hall Mark C. 

TITLE=Cdc14 phosphatase contributes to cell wall integrity and pathogenesis in Candida albicans

JOURNAL=Frontiers in Microbiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2023.1129155

DOI=10.3389/fmicb.2023.1129155

ISSN=1664-302X

ABSTRACT=<p>The Cdc14 phosphatase family is highly conserved in fungi. In <italic>Saccharomyces cerevisiae,</italic> Cdc14 is essential for down-regulation of cyclin-dependent kinase activity at mitotic exit. However, this essential function is not broadly conserved and requires only a small fraction of normal Cdc14 activity. Here, we identified an invariant motif in the disordered C-terminal tail of fungal Cdc14 enzymes that is required for full enzyme activity. Mutation of this motif reduced Cdc14 catalytic rate and provided a tool for studying the biological significance of high Cdc14 activity. A <italic>S. cerevisiae</italic> strain expressing the reduced-activity hypomorphic mutant allele (<italic>cdc14<sup>hm</sup></italic>) as the sole source of Cdc14 proliferated like the wild-type parent strain but exhibited an unexpected sensitivity to cell wall stresses, including chitin-binding compounds and echinocandin antifungal drugs. Sensitivity to echinocandins was also observed in <italic>Schizosaccharomyces pombe</italic> and <italic>Candida albicans</italic> strains lacking <italic>CDC14</italic>, suggesting this phenotype reflects a novel and conserved function of Cdc14 orthologs in mediating fungal cell wall integrity. In <italic>C. albicans,</italic> the orthologous <italic>cdc14<sup>hm</sup></italic> allele was sufficient to elicit echinocandin hypersensitivity and perturb cell wall integrity signaling. It also caused striking abnormalities in septum structure and the same cell separation and hyphal differentiation defects previously observed with <italic>cdc14</italic> gene deletions. Since hyphal differentiation is important for <italic>C. albicans</italic> pathogenesis, we assessed the effect of reduced Cdc14 activity on virulence in <italic>Galleria mellonella</italic> and mouse models of invasive candidiasis. Partial reduction in Cdc14 activity <italic>via cdc14<sup>hm</sup></italic> mutation severely impaired <italic>C. albicans</italic> virulence in both assays. Our results reveal that high Cdc14 activity is important for <italic>C. albicans</italic> cell wall integrity and pathogenesis and suggest that Cdc14 may be worth future exploration as an antifungal drug target.</p>