Core histones govern echinocandin susceptibility in Candida glabrata

Document Type

Article

Publication Title

Microbiology Spectrum

Abstract

The dynamic chromatin structure regulates many biological processes including gene expression, DNA repair, and genome stability in eukaryotic cells. However, its role in governing antifungal drug susceptibility in medically important fungi is just beginning to be deciphered. Chromatin architecture is maintained by a complex interplay among histone protein stoichiometry sustainment, post-translational modifications of histone proteins, and the activity of chromatin remodeling complexes. Herein, we report that the reduced gene dosage of histone core proteins in the opportunistic human fungal pathogen Candida glabrata leads to increased susceptibility toward the widely used, cell wall-targeting echinocandin antifungal drugs. Our comprehensive characterization of single and double histone mutants revealed that linker histone H1 loss had no effect on cell physiology and drug susceptibility, whereas low H2A, H2B, H3, and H4 protein levels resulted in decreased reactive oxygen species production, altered biofilm production, elevated DNA damage, and echinocandin stress susceptibility. Importantly, not all core histone mutants exhibited an increased sensitivity to other cell wall stressors, thereby precluding a general cell wall defect accounting solely for the increased caspofungin susceptibility. Finally, we show that the histone H3 acetylation at lysine-56 may be pivotal to caspofungin response of C. glabrata, as H3K56Ac levels were reduced in both core histone mutants and upon caspofungin exposure, with H3K56 acetyltransferase (CgRtt109)- and nucleosome assembly factor (CgAsf1)-lacking mutants displaying increased caspofungin susceptibility. Besides demonstrating the histone requirement for the survival of C. glabrata in the mouse systemic candidiasis model, our findings unveil histone dosage-regulated cellular processes that impact echinocandin susceptibility.

DOI

10.1128/spectrum.02399-24

Publication Date

6-1-2025

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