Dsc Orthologs Are Required for Hypoxia Adaptation, Triazole Drug Responses, and Fungal Virulence in Aspergillus fumigatus
ABSTRACTHypoxia is an environmental stress encountered byAspergillus fumigatusduring 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. fumigatusthat are orthologs of theSchizosaccharomyces pombegenesdsc1,dsc2,dsc3, anddsc4(dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage.A. fumigatusnulldscA-Dmutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes inS. pombe, both ΔdscAand ΔdscCresulted in reduced cleavage of the SrbA precursor protein inA. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscAand ΔdscCstrains revealed that these genes are critical forA. fumigatusvirulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscAstrain 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. fumigatusthat mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.