The Protein Kinase Tor1 Regulates Adhesin Gene Expression in Candida albicans

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Abstract
Eukaryotic cell growth is coordinated in response to nutrient availability, growth factors, and environmental stimuli, enabling cell–cell interactions that promote survival. The rapamycin-sensitive Tor1 protein kinase, which is conserved from yeasts to humans, participates in a signaling pathway central to cellular nutrient responses. To gain insight into Tor-mediated processes in human fungal pathogens, we have characterized Tor signaling in Candida albicans. Global transcriptional profiling revealed evolutionarily conserved roles for Tor1 in regulating the expression of genes involved in nitrogen starvation responses and ribosome biogenesis. Interestingly, we found that in C. albicans Tor1 plays a novel role in regulating the expression of several cell wall and hyphal specific genes, including adhesins and their transcriptional repressors Nrg1 and Tup1. In accord with this transcriptional profile, rapamycin induced extensive cellular aggregation in an adhesin-dependent fashion. Moreover, adhesin gene induction and cellular aggregation of rapamycin-treated cells were strongly dependent on the transactivators Bcr1 and Efg1. These findings support models in which Tor1 negatively controls cellular adhesion by governing the activities of Bcr1 and Efg1. Taken together, these results provide evidence that Tor1-mediated cellular adhesion might be broadly conserved among eukaryotic organisms. Living organisms have an intrinsic ability to coordinate their growth and proliferation in response to nutrient availability. In organisms ranging from yeasts to humans, the Tor1 signaling pathway responds to nutrient-derived signals and orchestrates cell growth. Accordingly, we find that in the human fungal pathogen Candida albicans, Tor1 signaling also functions to promote growth. We also uncovered a novel role for the Tor1 molecular pathway in promoting hyphal growth of C. albicans on semi-solid surfaces and in controlling cell–cell adherence. Gene expression analysis and genetic manipulations implicate the known cell surface adhesins Als1 and Als3 as mediators of Tor1-regulated cellular adhesion. Further genetic analysis identified the transcriptional regulators Bcr1, Efg1, Nrg1, and Tup1 that together with Tor1 compose a regulatory network governing adhesin gene expression and cellular adhesion. Given that the Tor pathway is the target of several small molecule inhibitors including rapamycin, a versatile pharmacological drug used in medicine, there is considerable interest in Tor signaling pathways and their function. Moreover, given the potent fungicidal activity of rapamycin against C. albicans, novel antifungal therapies remain to be developed, which may also include novel antifungal therapies with less immunosuppressive rapamycin analogs.

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