Control of the C. albicans Cell Wall Damage Response by Transcriptional Regulator Cas5

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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. For microbial pathogens, the cell wall is critical for interaction with both host and environment. The major fungal pathogen, Candida albicans, has a cell wall that resembles that of the model yeast Saccharomyces cerevisiae, and much of what is known about C. albicans cell wall biogenesis and repair comes via extrapolation from S. cerevisiae. Here, Bruno and colleagues inquired directly into the mechanisms that C. albicans uses to respond to disruption of cell wall biogenesis by the antifungal drug caspofungin, using a genetic strategy newly developed for C. albicans. They found that the response itself has many similarities to that of S. cerevisiae, but the regulatory circuitry is distinct: the major C. albicans regulatory gene has no clear counterpart among S. cerevisiae genes. Their findings provide a new example of a unique C. albicans regulatory function and one that may prove useful in identifying new drugs and in understanding possible resistance mechanisms.