title: Divergent Protein Kinase A isoforms co-ordinately regulate conidial germination, carbohydrate metabolism and virulence in Aspergillus fumigatus.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Fuller
authors.forename: Daryl L
authors.initials: DL
authors.lastname: Richie
authors.forename: Xizhi
authors.initials: X
authors.lastname: Feng
authors.forename: Karthik
authors.initials: K
authors.lastname: Krishnan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stephens
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.forename: David S
authors.initials: DS
authors.lastname: Askew
authors.forename: Judith C
authors.initials: JC
authors.lastname: Rhodes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001232:Aspergillus fumigatus / Q000201:enzymology / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D050260:Carbohydrate Metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D005947:Glucose / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D012331:RNA, Fungal / Q000235:genetics; D017384:Sequence Deletion; D013172:Spores, Fungal / Q000235:genetics / Q000254:growth & development*; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D007527:Isoenzymes; D012331:RNA, Fungal; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose