Investigation of the function of acetylation and crotonylation readers in Aspergillus fumigatus

• Grant number: 24/03816-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: February 01, 2025
• End date: February 29, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: André Ricardo de Lima Damasio
• Grantee: Gabriela Bassi da Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Diseases caused by fungi cause approximately 1.5 million deaths every year, affecting mainly immunocompromised patients. The Aspergillus fumigatus species is responsible for a large proportion of serious infections such as Invasive Aspergillosis (IA). Current treatment options are limited and a large number of cases of antifungal resistance have been reported, so finding new targets and improving the understanding of fungal pathogenesis are important prospects. Post-translational modifications, such as acylations, are involved in the virulence mechanism of pathogenic fungi. Among the acylations, acetylation and crotonylation of lysines have been described as modifications involved in various biological processes such as metabolism, cell cycle and organization. The dynamics of acetylation and crotonylation occur through the action of acetyl/crotonyltransferases or "writers", deacetylases/decrotonylases or "erasers", and epigenetic readers or "readers". It was recently demonstrated in Candida albicans that the Bdf1 protein (acetylation reader of the BET family) is essential and that mutations in the bromodomain (BD) domains resulted in loss of viability in vitro and reduced virulence in a murine model. Similarly, crotonylation readers with YEATS, Taf14 and Yaf9 domains have been shown to be necessary for the virulence of C. albicans. Studies on A. fumigatus have not yet been reported, however, preliminary results show that sirtuins (class III lysine deacetylases or KDACs III) are involved in acetylation and may be involved in crotonylation dynamics. Furthermore, in in vivo infection assays in Galleria mellonela and in mice, the deletion of AfSirE resulted in an attenuation of virulence among the six sirtuins of A. fumigatus. Therefore, our aim is to identify potential acetylation and crotonylation readers in A. fumigatus, generate mutants through gene deletion and characterize the role of these readers in the biology of the pathogen.