Dsc orthologs are required for hypoxia adaptation, triazole drug responses and fungal virulence in Aspergillus fumigatus

ABSTRACT

Hypoxia is an environmental stress encountered by Aspergillus fumigatus during invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA-D) with previous unknown functions in A. fumigatus that are orthologs of the Schizosaccharomyces pombe dsc1-4 genes, which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. A. fumigatus null mutants of dscA, B, C and D display remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with their confirmed role in S. pombe, both ΔdscA and ΔdscC have reduced cleavage of SrbA precursor protein in A. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscA and ΔdscC revealed that these genes are critical for A. fumigatus virulence. Re-introduction of SrbA amino acids 1-425, encoding the N-terminus DNA binding domain, into ΔdscA was able to partially restore virulence further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes in A. fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility that are likely linked to regulation of SrbA function.