Aspergillus fumigatus AcuM regulates both iron acquisition and gluconeogenesis.
Relatively few transcription factors that govern the virulence of Aspergillus fumigatus are known. We constructed 11 A. fumigatus transcription factor mutants and screened them for altered virulence in Galleria mellonella larvae. We discovered that the zinc cluster transcription factor, AcuM, is essential for maximal virulence in this model, as well as in murine models of haematogenously disseminated and invasive pulmonary aspergillosis. Transcriptional profiling experiments suggested that AcuM suppresses sreA and induces hapX to stimulate expression of genes involved in both reductive iron assimilation and siderophore-mediated iron uptake. Consistent with these results, a ΔacuM mutant had reduced iron incorporation, decreased extracellular siderophore production and impaired capacity to grow under iron-limited conditions. Interestingly, an Aspergillus nidulansΔacuM mutant had normal extracellular siderophore production and growth under iron-limited conditions, indicating that AcuM does not govern iron acquisition in this organism. A. fumigatus AcuM also regulated genes involved in gluconeogenesis, and the ΔacuM mutant had impaired growth on gluconeogenic carbon sources. Deletion of sreA in the ΔacuM mutant restored iron uptake, extracellular siderophore production and virulence, but not the defect in gluconeogenesis. Thus, AcuM represses SreA and thereby induces iron acquisition, a process that is essential for the maximal virulence of A. fumigatus.
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Hong
H
Liu
Fabrice N
FN
Gravelat
Lisa Y
LY
Chiang
Dan
D
Chen
Ghyslaine
G
Vanier
Daniele E
DE
Ejzykowicz
Ashraf S
AS
Ibrahim
William C
WC
Nierman
Donald C
DC
Sheppard
Scott G
SG
Filler
D000818:Animals; D001232:Aspergillus fumigatus / Q000378:metabolism* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005943:Gluconeogenesis; D007501:Iron / Q000378:metabolism*; D007814:Larva / Q000382:microbiology; D007915:Lepidoptera / Q000382:microbiology; D051379:Mice; D055732:Pulmonary Aspergillosis / Q000382:microbiology / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
D005656:Fungal Proteins; D012097:Repressor Proteins; D007501:Iron