Sirtuin E deacetylase is required for full virulence of Aspergillus fumigatus

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Wassano, Natalia S. ; da Silva, Gabriela B. ; Reis, Artur H. ; Gerhardt, Jaqueline A. ; Antoniel, Everton P. ; Akiyama, Daniel ; Rezende, Caroline P. ; Neves, Leandro X. ; Vasconcelos, Elton J. R. ; de Figueiredo, Fernanda L. ; Almeida, Fausto ; de Castro, Patricia A. ; Pinzan, Camila F. ; Goldman, Gustavo H. ; Leme, Adriana F. Paes ; Fill, Taicia P. ; Moretti, Nilmar S. ; Damasio, Andre

• Document type: Journal article
• Source: COMMUNICATIONS BIOLOGY; v. 7, n. 1, p. 17-pg., 2024-06-08.

Abstract

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. (AU)

• FAPESP's process: 18/09948-0 - Study of protein acetylation in Leishmania
• Grantee: Nilmar Silvio Moretti
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/06151-4 - Biology of NAD+-dependent lysine deacetylases (Sirtuins) in Aspergillus fumigatus
• Grantee: André Ricardo de Lima Damasio
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/03075-0 - Unraveling the regulatory mechanisms of host-parasite interaction of Leishmania: focus on post-transcriptional and post-translational changes
• Grantee: Nilmar Silvio Moretti
• Support Opportunities: Research Grants - Initial Project
• FAPESP's process: 21/04977-5 - The identification of new pathways and compounds that can enhance caspofungin activity against Aspergillus fumigatus
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/02992-0 - Deciphering the role of secondary metabolites in the chemical interaction between phytopathogens and the citrus host
• Grantee: Taicia Pacheco Fill
• Support Opportunities: Research Grants - Initial Project
• FAPESP's process: 22/05731-2 - BEYOND: establishing a fungal cell factory for recombinant protein production
• Grantee: André Ricardo de Lima Damasio
• Support Opportunities: Research Projects - Thematic Grants