Dissecting the structure of the ATP sulfurylase protein encoded by the MET3 gene and its relationship with the Cys3 transcription factor for the virulence of C. neoformans

• Grant number: 21/00725-1
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): July 01, 2021
• Effective date (End): January 31, 2023
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Renata Castiglioni Pascon
• Grantee: Jeyson Pereira da Silva
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

Cryptococcus neoformans is considered an opportunistic pathogenic fungus that causesseveral infections in immunocompromised patients and is the etiologic agent of cryptococcalmeningitis. Due to the small number of antifungals used in the clinic and the growingappearance of isolates resistant to therapeutic treatments and pharmacological agents, thesearch for knowledge about the mechanisms in which this pathogen is able to develop toevade the host's immune system and progress its infection is essential for the development ofmore efficient antifungals. In this context, the mechanisms of sulfur uptake and thebiosynthetic pathways of sulfurous amino acids have been studied, due to their alreadyreported importance on the virulence and permanence of C. neoformans in the host. Inaddition, this biosynthetic route does not occur in humans or animals affected bycryptococcosis, which contributes to future searches for more selective inhibitors. Previouswork by the UNIFESP Microbial Interactions Laboratory (LIMic - UNIFESP) revealedseveral aspects of the regulation of this pathway, mainly by revealing the role of thetranscription factor Cys3 in controlling the expression of several genes in this pathway, whichare crucial for virulence and pathogenesis. Its presence is mainly in the cell nucleus in thepresence of inorganic sulfur. Cys3 is part of a protein complex formed by the phosphatasescalcineurina and Gpp2. Recent studies by LIMic have shown that the transcription factorCys3 physically interacts with ATP sulforylase, encoded by the MET3 gene. This protein isresponsible for the first step of the inorganic sulfur uptake pathway, promoting adeninesulforylation. However, the existing interaction between these components of the biosyntheticpathway deserves further clarification. For all this presented, this project has as mainobjective to better understand the relationship between ATP sulfurylase, the transcriptionfactor Cys3 and calcineurin, as well as its implications for the sulfur uptake pathway andbiosynthesis of sulfur amino acids. We hope to expand the knowledge about the spectrum ofinteractions of Met3 with other proteins and add new results to the LIMic investigations,which are relevant for the discovery of new therapeutic forms against cryptococcosis andother systemic mycoses.