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

• Tipo de documento: Artigo Científico
• Fonte: COMMUNICATIONS BIOLOGY; v. 7, n. 1, p. 17-pg., 2024-06-08.

Resumo

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)

• Processo FAPESP: 18/09948-0 - Estudo da acetilação proteica em Leishmania
• Beneficiário: Nilmar Silvio Moretti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/06151-4 - Biologia de lisina desacetilases dependentes de NAD+ (sirtuinas) em Aspergillus fumigatus
• Beneficiário: André Ricardo de Lima Damasio
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 22/03075-0 - Desvendando os mecanismos regulatórios envolvidos na relação parasito hospedeiro da Leishmania: foco nas alterações pós-transcricionais e pós-traducionais
• Beneficiário: Nilmar Silvio Moretti
• Modalidade de apoio: Auxílio à Pesquisa - Projeto Inicial
• Processo FAPESP: 21/04977-5 - A identificação de vias metabólicas e compostos químicos que podem potenciar a ação de caspofungin contra Aspergillus fumigatus
• Beneficiário: Gustavo Henrique Goldman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 22/02992-0 - Decifrando o papel de metabólitos secundários na interação química entre fitopatógenos e o hospedeiro citros
• Beneficiário: Taicia Pacheco Fill
• Modalidade de apoio: Auxílio à Pesquisa - Projeto Inicial
• Processo FAPESP: 22/05731-2 - BEYOND: estabelecendo uma fábrica celular fúngica para produção de proteínas recombinantes
• Beneficiário: André Ricardo de Lima Damasio
• Modalidade de apoio: Auxílio à Pesquisa - Temático