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ATP sulfurylase: its relation to the Cys3 transcription factor and the regulation of the biosynthesis of sulfur amino acids in Cryptococcus neoformans

Grant number: 19/12051-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2019
Effective date (End): September 30, 2020
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal researcher:Renata Castiglioni Pascon
Grantee:Mariana Reis Meneghini
Home Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

C. neoformans is an opportunistic yeast that attacks immunocompromised patientscausing lethal infections such as cryptococcal meningitis. As a result of the resistance ofthe pathogens to the current medications and the lack of antifungals and effectivetreatments, the study on virulence mechanisms of C. neoformans is extremely importantto medicine. Yeasts are eukaryotes as well as their hosts, making the identification ofnew pharmacological drugs with high selective toxicity very difficult. The sulfur aminoacid biosynthesis pathway is exclusive to bacteria, plants, parasites and fungi. It is alsoextremely important to the survival of C. neoformans in vitro and in vivo and representsa potential target of inhibitors with high selective toxicity. The regulatory mechanismsof this biosynthesis route have been studied extensively, and the central transcriptionfactor, Cys3, controls the activation of several genes of this biosynthetic pathway. Ourprevious studies of immunopreciptation and mass spectrometry have shown that Cys3 ispart of a complex containing many proteins. Among these, two phosphatases(calcineurin and Gpp2 phosphatase), were confirmed as being part of this regulatorycomplex. A fourth protein called ATP sulfurylase was identified, but it has not yet beenconfirmed as a participant of this protein complex. This project is based on thehypothesis that the ATP sulfurylase encoded by the MET3 gene interacts physicallywith the Cys3 protein modulating the activation of the sulfur uptake pathway and thesulfurous amino acid biosynthesis. This hypothesis will be tested by a gene deletiontechnique, western blot, fluorescence microscopy and double hybrid in yeasts. All thesetechniques are routinely used at Laboratório de Interações Microbianas da UNIFESP. Itis expected that with this study it will be possible to know better the regulatorymechanisms of this pathway that is so important for virulence.

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