Spt7 Deletion Reveals Vulnerabilities in Cryptococcus neoformans Stress Adaptation and Virulence

TL;DR

Deleting the Spt7 gene in Cryptococcus neoformans weakens its ability to adapt to stress and causes loss of virulence, making it a potential target for antifungal treatments.

Contribution

This study identifies Spt7 as a key regulator of SAGA-mediated chromatin and virulence functions in Cryptococcus neoformans.

Findings

Spt7 deletion causes defects in melanization, capsule formation, and titan cell development.

The spt7Δ mutant is highly sensitive to antifungal drugs and environmental stresses.

Spt7 is essential for virulence in a mouse model and regulates chromatin modifications and proteomic balance.

Abstract

The Spt-Ada-Gcn5 acetyltransferase (SAGA) complex is a conserved transcriptional coactivator that coordinates histone modifications and transcriptional regulation in eukaryotes. In Cryptococcus neoformans, SAGA governs key virulence traits, yet the roles of several core scaffold subunits remain undefined. Here, we characterize the functional roles of Spt7, a core SAGA component, in C. neoformans. Comparative genomics revealed that C. neoformans Spt7 retains conserved histone fold and bromodomain motifs. Deletion of SPT7 produced pleiotropic phenotypes, including defective melanization and capsule formation, impaired titan cell development, and heightened sensitivity to thermal, metal, antifungal, and cell wall stresses. The spt7Δ mutant exhibited strong sensitivity to the echinocandin micafungin, implicating Spt7 in maintaining cell wall integrity. The spt7Δ mutant was avirulent in a murine inhalation model. At the chromatin level, SPT7 deletion disrupted SAGA-dependent histone post-translational modifications, increasing H2B ubiquitination while reducing H3K14ac and H3K18ac levels. Proteomic profiling revealed reduced abundance of ribosomal, mitochondrial, and translational proteins and upregulation of lipid metabolic and secretory pathway components. Collectively, our findings establish Spt7 as a central integrator of SAGA-mediated chromatin regulation, proteomic balance, and virulence in C. neoformans and highlight the SAGA core as a potential antifungal target.

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