Abstract
The fungal cell wall is vital for growth, development, and interaction of cells with their environment. The response to cell wall damage is well understood from studies in the budding yeast Saccharomyces cerevisiae, where numerous cell wall integrity (CWI) genes are activated by transcription factor ScRlm1. Prior evidence suggests the hypothesis that both response and regulation may be conserved in the major fungal pathogen Candida albicans. We have tested this hypothesis by using a new C. albicans genetic resource: we have screened mutants defective in putative transcription factor genes for sensitivity to the cell wall biosynthesis inhibitor caspofungin. We find that the zinc finger protein CaCas5, which lacks a unique ortholog in S. cerevisiae, governs expression of many CWI genes. CaRlm1 has a modest role in this response. The transcriptional coactivator CaAda2 is also required for expression of many CaCas5-dependent genes, as expected if CaCas5 recruits CaAda2 to activate target gene transcription. Many caspofungin-induced C. albicans genes specify endoplasmic reticulum and secretion functions. Such genes are not induced in S. cerevisiae, but promote its growth in caspofungin. We have used a new resource to identify a key C. albicans transcriptional regulator of CWI genes and antifungal sensitivity. Our gene expression findings indicate that both divergent and conserved response genes may have significant functional roles. Our strategy may be broadly useful for identification of pathogen-specific regulatory pathways and critical response genes.
Highlights
The cell wall is critical for the interaction of fungal cells with their environment
In order to identify C. albicans regulators of the cell wall damage response, we screened among mutants homozygous for insertions in 83 putative transcription factor genes [16] for altered growth on medium containing caspofungin
Caspofungin-Responsive Gene Function in C. albicans Our current understanding of fungal cell wall damage responses comes largely from studies in S. cerevisiae, an essential point of comparison
Summary
The cell wall is critical for the interaction of fungal cells with their environment. It provides a resilient framework that permits survival over a wide range of environmental conditions. It is the point of contact between fungal cells and surfaces to which they may bind. As the determinant of fungal cell shape, it is modified during morphogenetic programs, including budding, mating, hypha production, sporulation, and host invasion by pathogens; genes specifying cell wall proteins and biogenesis enzymes are major targets of developmental regulatory pathways. As a distinguishing fungal structure, the cell wall is the target of natural antifungal metabolites and derivatives of growing therapeutic utility. An understanding of the cell wall and its regulation is relevant to fungal ecology, development, and pathogenesis
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