Triazole Stress Induces Accelerated Degradation of Aspergillus fumigatus Hmg1

Abstract

Triazole antifungals inhibit the lanosterol C14-demethylase Cyp51A/B and are the first-line treatment for invasive aspergillosis caused by Aspergillus fumigatus. We previously proposed that triazoles impose a secondary constraint on ergosterol biosynthesis through negative feedback regulation of HMG-CoA reductase (Hmg1) through its sterol sensing domain (SSD), and SSD mutations compromise this regulation to produce resistance. The molecular mechanism underpinning this feedback remained unknown. In this study, we show that voriconazole drives accelerated protein degradation of Hmg1 and that SSD mutation abolishes this regulated degradation. Triazole-induced Hmg1 degradation is proteasome-dependent and partially requires the ERAD E3 ubiquitin ligase, HrdA, and INSIG ortholog, InsA, both conserved regulators of HMG-CoA Reductase abundance. We provide genetic evidence that the initiating negative feedback signal is not triazole acting directly on Hmg1 but lanosterol accumulation resulting from Cyp51A/B inhibition. To test whether depleting Hmg1 protein could re-sensitize resistant strains, we utilized a GFP-targeted degradation system designed to target Hmg1 for degradation without engaging its SSD. Combining this system with voriconazole treatment reduced the MIC at least four-fold in both conidia and established hyphae in susceptible and resistant strains. Together, our findings support a model wherein triazole-induced lanosterol accumulation drives HrdA/InsA-dependent accelerated degradation of Hmg1 and establish that pharmacologically inducing this secondary mechanism can enhance triazole activity in both susceptible and resistant isolates.

Ribosomal biogenesis factor links ribosome homeostasis to host relevant stress survival in Aspergillus fumigatus
J. A. Adeoye, H. Hayby, N. Shlezinger
bioRxiv25 Oct 2026PreprintAll rights reservedFull textMicrobiologybioRxiv
The self-sufficient Aspergillus fumigatus Δ9-fatty acid desaturase SdeA requires a fused cytochrome b5 domain and hinge-dependent self-association for virulence
J. E. M. Campanella, G. Y. Filho, J. H. T. M. Fabri +6
bioRxiv23 Oct 2026PreprintAll rights reservedFull textMicrobiologybioRxiv
3' Plasma Membrane Phosphoinositides Sustain ROS Production at Persistent Non-canonical Phagocytic Cups that Promote Macrophage Control of Aspergillus fumigatus Hyphae
S. Moussaoui, M. C. Gimenez, A. Paixao +6
bioRxiv14 Sep 2026PreprintCC BY-NC-NDFull textCell biologybioRxiv
GM-CSF signaling on monocytes and monocyte-derived dendritic cells is required for effective pulmonary immunity to Aspergillus fumigatus
K. A. M. Mills, B. Becher, T. M. Hohl
bioRxiv22 Sep 2026PreprintCC BYFull textImmunologybioRxiv
Biotinylation-dependent near-neighbor analysis for identification of septation regulators in Aspergillus fumigatus
H. I. Thorn, A. Martin-Vicente, U. Perez-Cuesta +4
bioRxiv17 Sep 2026PreprintCC BYFull textMicrobiologybioRxiv

Cite

BibTeX RIS

BibTeX

@misc{xie2026triazole,
  title = {{Triazole Stress Induces Accelerated Degradation of Aspergillus fumigatus Hmg1}},
  author = {J. Xie and A. Martin-Vicente and H. I. Thorn and U. Perez-Cuesta and A. Nandi and J. R. Fortwendel},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.02.756251},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756251v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Triazole Stress Induces Accelerated Degradation of Aspergillus fumigatus Hmg1
AU  - J. Xie
AU  - A. Martin-Vicente
AU  - H. I. Thorn
AU  - U. Perez-Cuesta
AU  - A. Nandi
AU  - J. R. Fortwendel
PY  - 2026
DA  - 2026/10/02
PB  - bioRxiv
DO  - 10.64898/2026.10.02.756251
UR  - https://www.biorxiv.org/content/10.64898/2026.10.02.756251v1
AB  - Triazole antifungals inhibit the lanosterol C14-demethylase Cyp51A/B and are the first-line treatment for invasive aspergillosis caused by Aspergillus fumigatus. We previously proposed that triazoles impose a secondary constraint on ergosterol biosynthesis through negative feedback regulation of HMG-CoA reductase (Hmg1) through its sterol sensing domain (SSD), and SSD mutations compromise this regulation to produce resistance. The molecular mechanism underpinning this feedback remained unknown. In this study, we show that voriconazole drives accelerated protein degradation of Hmg1 and that SSD mutation abolishes this regulated degradation. Triazole-induced Hmg1 degradation is proteasome-dependent and partially requires the ERAD E3 ubiquitin ligase, HrdA, and INSIG ortholog, InsA, both conserved regulators of HMG-CoA Reductase abundance. We provide genetic evidence that the initiating negative feedback signal is not triazole acting directly on Hmg1 but lanosterol accumulation resulting from Cyp51A/B inhibition. To test whether depleting Hmg1 protein could re-sensitize resistant strains, we utilized a GFP-targeted degradation system designed to target Hmg1 for degradation without engaging its SSD. Combining this system with voriconazole treatment reduced the MIC at least four-fold in both conidia and established hyphae in susceptible and resistant strains. Together, our findings support a model wherein triazole-induced lanosterol accumulation drives HrdA/InsA-dependent accelerated degradation of Hmg1 and establish that pharmacologically inducing this secondary mechanism can enhance triazole activity in both susceptible and resistant isolates.
ER  -

Abstract

Related

Cite