Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus

Hypoxia is an environmental stress encountered byAspergillus 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 ,dscB ,dscC , anddscD , here referred to asdscA-D ) with previously unknown functions inA. fumigatus that are orthologs of theSchizosaccharomyces pombe genesdsc1 ,dsc2 ,dsc3 , anddsc4 (dsc1-4 ), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage.A. fumigatus nulldscA-D mutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes inS. pombe , both ΔdscA and ΔdscC resulted in reduced cleavage of the SrbA precursor protein inA. fumigatus . Inoculation of corticosteroid immunosuppressed mice with ΔdscA and ΔdscC strains revealed that these genes are critical forA. fumigatus virulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscA strain 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 inA. fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.