1887

Abstract

The human pathogen adapts to stress encountered in the mammalian host as part of its ability to cause disease. The transcription factor SrbA plays a significant role in this process by regulating genes involved in hypoxia and low-iron adaptation, antifungal drug responses and virulence. SrbA is a direct transcriptional regulator of genes encoding key enzymes in the ergosterol biosynthesis pathway, including and , and Δ accumulates C4-methyl sterols, suggesting a loss of Erg25 activity [C4-sterol methyl oxidase (SMO)]. Characterization of the two genes encoding SMOs in revealed that both serve as functional C4-demethylases, with Erg25A serving in a primary role, as Δ accumulates more C4-methyl sterol intermediates than Δ. Single deletion of these SMOs revealed alterations in canonical ergosterol biosynthesis, indicating that ergosterol may be produced in an alternative fashion in the absence of SMO activity. A Δ strain displayed moderate susceptibility to hypoxia and the endoplasmic reticulum stress-inducing agent DTT, but was not required for virulence in murine or insect models of invasive aspergillosis. Inducing expression of partially restored the hypoxia growth defect of Δ. These findings implicated SMOs in the maintenance of canonical ergosterol biosynthesis and indicated an overall involvement in the fungal stress response.

Funding
This study was supported by the:
  • , NIH/NIAID , (Award R01AI81838)
  • , NIH/NIGMS , (Award COBRE GM103500)
  • , American Heart Association , (Award 10PRE2700014 and 12PRE8690007)
  • , NIH/NIGMS , (Award COBRE P20 RR024237)
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2014-11-01
2021-03-05
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