Proteomics

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Mod5 mediates a molecular trade-off between optimal gene expression and antifungal resistance


ABSTRACT: Increasing antifungal drug resistance is a major concern associated with human fungal infections. Genetic mutation and epimutation mechanisms are clearly linked to resistance in some fungi, but few studies have investigated RNA modifications (the epitranscriptome) as a mediator of resistance. Here, deletion of the Aspergillus fumigatus tRNA-modifying isopentenyl transferase ortholog, Mod5, led to altered growth and stress response, but also unexpected resistance against the antifungal drug 5-fluorocytosine (5-FC). Simultaneous profiling of the transcriptome and proteome of 5-FC-stressed wild-type and ∆mod5 strains revealed a similar general adaptation to stress; however, the knockout displayed elevated expression of cross-pathway control (CPC) genes. Quantification of CPC transcription factor cpcA and client gene argB showed premature CPC activation in ∆mod5, which was further increased upon treatment with 5-FC. By associating codon usage patterns with proteomics abundances, we observed the number of tRNATyrGΨA-decoded codons to negatively correlate with protein abundance in the knockout, indicative of modification-tuneable transcripts. Subsequent overexpression of tRNATyrGΨA in the ∆mod5 strain rescued select phenotypes but, surprisingly, failed to reverse 5-FC resistance. Investigation of the purported tRNA gene-mediated silencing function of Mod5 uncovered a negative correlation between tRNA proximity and gene induction under normal growth, suggesting that tRNA gene-mediated silencing is active in A. fumigatus. In conclusion, 5-FC resistance in the absence of the bifunctional Mod5 protein likely originates from multifaceted transcriptional and translational changes that skew the fungus towards starvation responses over optimal growth, potentially offering a mechanism reliant on RNA modification and tRNA gene-mediated silencing capable of facilitating transient antifungal resistance.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Aspergillus Fumigatus Cea17

SUBMITTER: Thomas Krüger  

LAB HEAD: Axel A. Brakhage

PROVIDER: PXD048351 | Pride | 2024-10-23

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
A_WT_1-a.raw Raw
A_WT_1-b.raw Raw
A_WT_1-c.raw Raw
A_WT_2-a.raw Raw
A_WT_2-b.raw Raw
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