![]() To activate the enzyme, two molecules of cAMP bind to the regulatory subunits and trigger conformational changes that dissociate the complex, resulting in activation of the catalytic subunits of PKA for subsequent phosphorylation of substrates in various subcellular compartments. The catalytic subunits are encoded by the TPK1-3 genes and the regulatory subunit is encoded by the BCY1 gene ( Toda et al., 1987a, b). cerevisiae activate the adenylyl cyclase Cyr1 to produce cAMP that in turn activates PKA, a heterotetrameric protein comprised of two catalytic and two regulatory subunits. Integration of information from these lines of investigation led to the view that Ras proteins mediate intracellular glucose sensing in a glycolysis-dependent manner, whereas extracellular glucose is sensed through a G-protein coupled receptor (GPCR) system ( Thevelein and de Winde, 1999). The framework of the pathway emerged from two lines of research in this yeast: (1) the identification of the signaling functions of the oncogenic mammalian Ras protein using yeast as a model system, and (2) the cAMP-induced phosphorylation of trehalase, an enzyme involved in trehalose mobilization in fungi ( Powers et al., 1984 Thevelein, 1984). The main components and functions of the cAMP/PKA pathway in nutrient sensing have been extensively characterized in the model yeast Saccharomyces cerevisiae ( Figure 1). For example, in fungi, the availability of nutrients such as glucose is sensed through a number of mechanisms including the cyclic AMP/protein kinase A (cAMP/PKA) signal transduction pathway. Signal transduction pathways play critical roles in mediating microbial adaptation. Challenging conditions in hosts include differences in nutrient availability, pH, oxygen levels, and temperature, as well as threats posed by the immune response. This is particularly true for pathogenic microbes because they must make the transition from the environment to host conditions and mount an appropriate response to establish an infection. The ability to rapidly adapt to changing external conditions is crucial for the survival and proliferation of microorganisms. Finally, we highlight recent studies that connect the cAMP/PKA pathway to cell surface remodeling and the formation of titan cells. neoformans including new insights emerging from the analysis of transcriptional and proteomic changes in strains with altered PKA activity and expression. We then discuss key features of cAMP/PKA signaling in C. In this review, we focus first on insights into the role of the cAMP/PKA pathway in nutrient sensing for the model yeast Saccharomyces cerevisiae to provide a foundation for understanding the pathway in C. For instance, protein kinase A (PKA) in the human pathogen Cryptococcus neoformans plays a central role in orchestrating phenotypic changes, such as capsule elaboration and melanin production, that directly impact disease development. ![]() Interestingly, the cAMP/PKA pathway in fungal pathogens also influences the expression of virulence determinants in response to nutritional and host signals. The conserved cAMP/PKA signaling pathway contributes to adaptation by sensing the availability of key nutrients such as glucose and directing changes in gene expression and metabolism. Nutrient sensing is critical for adaptation of fungi to environmental and host conditions. Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
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