MYCOLab Ai Logo - gold and army green

The transcription factor RttA contributes to sterol regulation and azole resistance in Aspergillus fumigatus

Summary

Researchers corrected the mislabeled rttA gene in the dangerous fungus Aspergillus fumigatus and discovered it acts as a master control switch for sterol production and antifungal drug resistance. When this gene is active, it helps fungi survive azole medications by boosting production of ergosterol, a critical component of fungal cell membranes. This discovery reveals how fungi develop resistance to our frontline antifungal treatments and suggests new ways to combat these life-threatening infections.

Background

Azole antifungals are frontline treatments against Aspergillus fumigatus, a major fungal pathogen causing life-threatening infections. Azole resistance in A. fumigatus commonly results from overexpression of cyp51A, regulated by transcription factors AtrR and SrbA that orchestrate ergosterol biosynthesis genes. Previous research identified rttA as a gene associated with azole tolerance but its function remained unclear due to incorrect annotation.

Objective

To identify and characterize the previously misannotated rttA gene and determine its role in sterol regulation and azole resistance in A. fumigatus. The study aimed to correct the gene annotation, establish RttA as a transcription factor, and elucidate its regulatory functions within the sterol biosynthesis pathway.

Results

RttA correction revealed a Zn₂Cys₆ binuclear zinc cluster transcription factor structurally similar to Upc2 and NcSR. rttA deletion reduced voriconazole MIC 2-fold while overexpression increased it 8-fold. RttA specifically activated erg6 expression, and its deletion led to lanosterol accumulation and ergosterol depletion during azole stress. rttA expression depended on both AtrR and SrbA, and erg6 upregulation partially restored azole tolerance in rttA deletion mutants.

Conclusion

RttA functions as a transcription factor regulating ergosterol biosynthesis and azole resistance in A. fumigatus through activation of erg6 and efflux pump genes. Its structural similarity to sterol regulators in yeast and Neurospora suggests a conserved mechanism of sterol-dependent regulation, positioning RttA within the regulatory network of AtrR and SrbA.
  • Published in:mBio,
  • Study Type:Experimental Research,
  • Source: PMID: 40937856, DOI: 10.1128/mbio.01854-25
Scroll to Top