Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus

• Published in: Communications biology Vol. 7; no. 1; pp. 704 - 17
• Main Authors: Wassano, Natália S., da Silva, Gabriela B., Reis, Artur H., A. Gerhardt, Jaqueline, Antoniel, Everton P., Akiyama, Daniel, Rezende, Caroline P., Neves, Leandro X., Vasconcelos, Elton J. R., de Figueiredo, Fernanda L., Almeida, Fausto, de Castro, Patrícia A., Pinzan, Camila F., Goldman, Gustavo H., Paes Leme, Adriana F., Fill, Taicia P., Moretti, Nilmar S., Damasio, André
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-06-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 38/39; 38/70; 38/71; 38/77; 42/41; 42/44; 631/326/193/2538; 631/326/421; 82/80; 82/83; Acetylation; Animals; Aspergillosis - drug therapy; Aspergillosis - microbiology; Aspergillus fumigatus; Aspergillus fumigatus - enzymology; Aspergillus fumigatus - genetics; Aspergillus fumigatus - pathogenicity; Biomedical and Life Sciences; Cell walls; Fungal Proteins - genetics; Fungal Proteins - metabolism; Gene deletion; Gene expression; Gene Expression Regulation, Fungal; Histones; Infections; Life Sciences; Mice; Moths - microbiology; Post-translation; Proteins; Public health; Sirtuins; Sirtuins - genetics; Sirtuins - metabolism; Temperature tolerance; Virulence; Virulence factors; Virulence Factors - genetics; Virulence Factors - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06383-3

Aspergillus fumigatus
represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD
+
-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus
A. fumigatus
remains unclear. This study constructs six single knockout strains of
A. fumigatus
and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins’ involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of
sirE
attenuates virulence in murine and
Galleria mellonella
infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat
A. fumigatus
infections or in combination therapy with available antifungals.
Sirtuin’s function was studied in
A. fumigatus
by creating knockout strains. SirE encoding gene deletion reduces virulence, alters protein acetylation and gene expression. Sirtuin inhibitors have potential as therapy for
A. fumigatus
infections.