A Sterol-Regulatory Element Binding Protein Is Required for Cell Polarity, Hypoxia Adaptation, Azole Drug Resistance, and Virulence in Aspergillus fumigatus

Abstract

At the site of microbial infections, the significant influx of immune effector cells and the necrosis of tissue by the invading pathogen generate hypoxic microenvironments in which both the pathogen and host cells must survive. Currently, whether hypoxia adaptation is an important virulence attribute of opportunistic pathogenic molds is unknown. Here we report the characterization of a sterol-regulatory element binding protein, SrbA, in the opportunistic pathogenic mold, Aspergillus fumigatus. Loss of SrbA results in a mutant strain of the fungus that is incapable of growth in a hypoxic environment and consequently incapable of causing disease in two distinct murine models of invasive pulmonary aspergillosis (IPA). Transcriptional profiling revealed 87 genes that are affected by loss of SrbA function. Annotation of these genes implicated SrbA in maintaining sterol biosynthesis and hyphal morphology. Further examination of the SrbA null mutant consequently revealed that SrbA plays a critical role in ergosterol biosynthesis, resistance to the azole class of antifungal drugs, and in maintenance of cell polarity in A. fumigatus. Significantly, the SrbA null mutant was highly susceptible to fluconazole and voriconazole. Thus, these findings present a new function of SREBP proteins in filamentous fungi, and demonstrate for the first time that hypoxia adaptation is likely an important virulence attribute of pathogenic molds.

Regulation of hypoxia adaptation: an overlooked virulence attribute of pathogenic fungi?

“…While our results strongly suggest that the virulence defect is due to the inability of this mutant to grow in hypoxia due to the loss of hypoxia adaptation mechanisms regulated by SrbA, as with C. neoformans, other potential hypotheses may explain the attenuation of virulence (124). For example, SrbA plays an important role in maintenance of cell polarity in A. fumigatus (124).…”

“…The SREBP pathway in Aspergillus fumigatus: Recently, our laboratory identified and characterized an SREBP (Sre1p) ortholog, SrbA, in A. fumigatus (124). As in C. neoformans, SrbA is crucial for adaptation to hypoxia, mediates resistance to the azole class of antifungal drugs and is involved in sterol biosynthesis in A. fumigatus ( Figure 2 and Figure 3).…”

Structural Requirements for Sterol Regulatory Element-binding Protein (SREBP) Cleavage in Fission Yeast

“…This motif is broadly conserved across ascomycete fungi, whose members lack homologs of the intramembrane-cleaving Site-2 protease present in mammals. These findings demonstrate a role for this conserved glycineleucine motif in fungal SREBP cleavage activation, provide tools for dissecting the mechanism of SREBP cleavage, and identify the SREBP C terminus as a target for antifungal therapy for pathogenic fungi that contain a relevant conserved SREBP pathway (5,7,9,14,15).…”

“…For instance, A. fumigatus is a major cause of life-threatening infections in immunocompromised individuals (33). Notably, A. fumigatus SREBP homolog SrbA as well as Dsc E3 ligase homologs are required for pathogenesis (7,13). Interestingly, the glycine-leucine motif is conserved in Aspergillus.…”

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

“…As in C. neoformans, SREBP was required for hypoxic growth, regulation of sterol biosynthetic enzymes, resistance to azole drugs, and fungal virulence (Willger et al 2008). Of note, A. fumigatus lacks a SCAP homolog but codes for Ofd1 (Table 1), suggesting that oxygen regulation of SREBP may be modular in fungi.…”