Divergent Protein Kinase A isoforms co-ordinately regulate conidial germination, carbohydrate metabolism and virulence in Aspergillus fumigatus. Mol Microbiol

Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA.
Molecular Microbiology (Impact Factor: 4.42). 02/2011; 79(4):1045-62. DOI: 10.1111/j.1365-2958.2010.07509.x
Source: PubMed


The genome of Aspergillus fumigatus encodes two isoforms of the catalytic subunit of the cAMP-dependent Protein Kinase (PKA). Although deletion of the class I isoform, pkaC1, leads to an attenuation of virulence, the function of the class II subunit, PkaC2, was previously uninvestigated. In this report, we demonstrate that both isoforms act in concert to support various physiologic processes that promote the virulence of this pathogen. Whereas pkaC1 and pkaC2 single-deletion mutants display wild-type conidial germination, a double-deletion mutant is delayed in germination in response to environmental nutrients. Furthermore, PkaC1 and PkaC2 interact to positively regulate flux through the carbohydrate catabolic pathway and, consequently, the ΔpkaC1ΔpkaC2 mutant is unable to grow on low glucose concentrations. Importantly, the reduced germinative capacity and inability to utilize glucose observed for the ΔpkaC1ΔpkaC2 strain correlated with an inability of the mutant to establish infection in a murine model. Conversely, overexpression of pkaC2 both promotes the in vitro growth on glucose, and restores the fungal burden and mortality associated with the ΔpkaC1 to that of the wild-type organism. Taken together, these data demonstrate the functional capacity of pkaC2 and emphasize the importance of PKA-mediated metabolic control in the pathogenic potential of A. fumigatus.

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    • "Overall, the connections between Hsp90 and additional pathways in A. fumigatus have not been fully investigated. The conserved role of cAMP signalling in regulating A. fumigatus development suggests that there may be an additional pathway by which Hsp90 can regulate germination and polarized hyphal growth (Fuller et al., 2011). "
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    • "So far investigations on homologues of FfPKA2 in other fungi revealed only a minor role in fungal development and virulence. For example, in A. fumigatus PKAC2 is involved in the regulation of germination, cell wall homeostasis and carbohydrate metabolism [76], while deletion of PkaB in A. nidulans and bcpka2 in B. cinerea did not result in any phenotypic alterations [77], [32]. However, deletion of both catalytic subunits is lethal in A. nidulans [77], indicating that the catalytic subunits can at least partially complement each other. "
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    • "In its natural environment, the soil, A. fumigatus represents a prime saprobe that is characterized by its metabolic versatility and great adaptability. It has been suggested that such a competitive environment has served as evolutionary virulence school for this fungal pathogen (Askew, 2008; Fuller et al., 2011). This implies that A. fumigatus expresses distinct features supporting growth in human tissues based on adaptation to the adverse and variable conditions commonly encountered in the wild. "
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