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Coordinated regulation of calcium homeostasis and pathogenicity by a dual-action transcriptional regulator Cas5 [RNA-Seq]

ABSTRACT: As a clinically relevant opportunistic human fungal pathogen, C. albicans is able to rapidly sense and adapt to changing microenvironments within the host, a process that is essential for its successful invasion and survival. Although studies have shown that the transcription factor Crz1 is the master regulator of calcium (Ca2+) homeostasis, accumulating evidence supports a clear involvement of other participants in this biological process. Here, following a high-throughput genetic screen, we identified the transcription factor Cas5 as a novel positive regulator of Ca2+ homeostasis in C. albicans. Mechanistically, Cas5 modulates Crz1 dephosphorylation, nuclear localization and Crz1-dependent signaling pathway by inhibiting protein kinase Tpk1 to maintain Ca2+ homeostasis. Furthermore, our study confirms that the calcineurin-mediated virulence is dependent on transcription factor Cas5 in a Crz1-independent manner, complementing a long-standing knowledge gap in the regulation of virulence by calcineurin. Taken together, our findings elucidate that a dual-action transcriptional regulator Cas5 coordinates both Ca2+ homeostasis and pathogenicity of C. albicans in the host.

ORGANISM(S): Candida albicans

PROVIDER: GSE295027 | GEO | 2026/04/18

REPOSITORIES: GEO

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Project description:Calcineurin is a highly conserved Ca2+/calmodulin-dependent serine/threonine-specific protein phosphatase that orchestrates cellular Ca2+ signaling responses. In Cryptococcus neoformans, calcineurin is activated by multiple stresses including high temperature, and is essential for stress adaptation and virulence. The transcription factor Crz1 is a major calcineurin effector in Saccharomyces cerevisiae and other fungi. Calcineurin dephosphorylates Crz1, thereby enabling Crz1 nuclear translocation and transcription of target genes. Here we show that Crz1 is dephosphorylated by calcineurin, and crz1Δ mutants display phenotypes intermediate between wild-type and calcineurin mutants. RNA-sequencing revealed 102 genes that are regulated in a calcineurin/Crz1-dependent manner at 37°C. 99 genes were down-regulated in cna1Δ and crz1Δ mutants, indicating these genes are normally activated by the calcineurin/Crz1 pathway at high temperature. About 58% of calcineurin-Crz1 target genes have unknown functions, while genes with known or predicted functions are involved in cell wall remodeling, calcium transport, and pheromone production. Surprisingly, only five genes have orthologs known to be calcineurin/Crz1-dependent in S. cerevisiae. 393 genes are independently regulated by calcineurin, and Crz1 regulates 59 genes independently of calcineurin. Taken together, these results indicate that the calcineurin/Crz1-dependent pathway controls a transcriptional circuit that has been extensively rewired in C. neoformans compared to S. cerevisiae. Given the intermediate crz1Δ mutant phenotype, and our recent evidence for a calcineurin regulatory network impacting mRNA in P-bodies and stress granules independently of Crz1, calcineurin likely acts on factors beyond Crz1 that govern mRNA expression/stability to operate a branched transcriptional/post-transcriptional stress response network necessary for fungal virulence. Taken together, our findings reveal the core calcineurin-Crz1 stress response cascade is maintained from ascomycetes to a pathogenic basidiomycete fungus, but its output has been extensively rewired to promote fungal virulence.

Project description:Exposure of the budding Saccharomyces cerevisiae to an alkaline environment produces a robust transcriptional response involving hundreds of genes. Part of this response is triggered by an almost immediate burst of calcium that activates the Ser/Thr protein phosphatase calcineurin. Activated calcineurin dephosphorylates the transcription factor Crz1, which moves to the nucleus and binds to calcineurin/Crz1 responsive gene promoters. In this work we present a genome-wide study of the binding of Crz1 to gene promoters in response to high pH stress. Environmental alkalinization promoted a time-dependent recruitment of Crz1 to 152 intergenic regions, the vast majority between 1 to 5 min upon stress onset. Positional evaluation of the genomic coordinates combined with existing transcriptional studies allowed identifying 139 genes likely responsive to Crz1 regulation. Gene Ontology analysis confirmed the relevant impact of calcineurin/Crz1 on a set of genes involved in glucose utilization, and uncovered novel targets, such as genes responsible for trehalose metabolism. We also identified over a dozen of genes encoding transcription factors that are likely under the control of Crz1, suggesting a possible mechanism for amplification of the signal at the transcription level. Further analysis of the binding sites allowed refining the consensus sequence for Crz1 binding to gene promoters and the effect of chromatin accessibility in the timing of Crz1 recruitment to promoters. The present work defines at the genomic-wide level the kinetics of binding of Crz1 to gene promoters in response to alkaline stress, confirms diverse previously known Crz1 targets and identifies many putative novel ones. Because the relevance of calcineurin/Crz1 in signaling diverse stress conditions, our data will contribute to understand the transcriptional response in other circumstances that also involves calcium signaling, such as exposition to sexual pheromones or saline stress.

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Coordinated regulation of calcium homeostasis and pathogenicity by a dual-action transcriptional regulator Cas5 [RNA-Seq]

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