Mitogen-Activated Protein Kinase Cross-Talk Interaction Modulates the Production of Melanins in Aspergillus fumigatus

Author(s):Show less -

Manfiolli, Adriana Oliveira ^[1] ; Siqueira, Filipe Silva ^[1] ; dos Reis, Thaila Fernanda ^[1] ; Van Dijck, Patrick ^{[2, 3]} ; Schrevens, Sanne ^{[2, 3]} ; Hoefgen, Sandra ^[4] ; Foege, Martin ^[5] ; Strassburger, Maria ^[6] ; de Assis, Leandro Jose ^[1] ; Heinekamp, Thorsten ^[5] ; Rocha, Marina Campos ^[7] ; Janevska, Slavica ^[4] ; Brakhage, Axel A. ^{[5, 8]} ; Malavazi, Iran ^[7] ; Goldman, Gustavo H. ^[1] ; Valiante, Vito ^{[4, 8]}

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Ribeirao Preto - Brazil

^[2] Katholieke Univ Leuven, Inst Bot & Microbiol, Lab Mol Cell Biol, Leuven - Belgium

^[3] VIB KU Leuven Ctr Microbiol, Flanders - Belgium

^[4] HKI, Leibniz Inst Nat Prod Res & Infect Biol, Leibniz Res Grp Biobricks Microbial Nat Prod Synt, Jena - Germany

^[5] HKI, Dept Mol & Appl Microbiol, Jena - Germany

^[6] HKI, Transfer Grp Antiinfect, Jena - Germany

^[7] Univ Fed Sao Carlos, Ctr Ciencias Biol & Saude, Dept Genet & Evolucao, Sao Carlos, SP - Brazil

^[8] Friedrich Schiller Univ, Jena - Germany

• Document type: Journal article
• Source: MBIO; v. 10, n. 2 MAR-APR 2019.
• Web of Science Citations: 0

Abstract

The pathogenic fungus Aspergillus fumigatus is able to adapt to extremely variable environmental conditions. The A. fumigatus genome contains four genes coding for mitogen-activated protein kinases (MAPKs), which are important regulatory knots involved in diverse cellular responses. From a clinical perspective, MAPK activity has been connected to salvage pathways, which can determine the failure of effective treatment of invasive mycoses using antifungal drugs. Here, we report the characterization of the Saccharomyces cerevisiae Fus3 ortholog in A. fumigatus, designated MpkB. We demonstrate that MpkB is important for conidiation and that its deletion induces a copious increase of dihydroxynaphthalene (DHN)-melanin production. Simultaneous deletion of mpkB and mpkA, the latter related to maintenance of the cell wall integrity, normalized DHN-melanin production. Localization studies revealed that MpkB translocates into the nuclei when A. fumigatus germlings are exposed to caspofungin stress, and this is dependent on the cross-talk interaction with MpkA. Additionally, DHN-melanin formation was also increased after deletion of genes coding for the G alpha protein GpaA and for the G protein-coupled receptor GprM. Yeast two-hybrid and coimmunoprecipitation assays confirmed that GpaA and GprM interact, suggesting their role in the MpkB signaling cascade. IMPORTANCE Aspergillus fumigatus is the most important airborne human pathogenic fungus, causing thousands of deaths per year. Its lethality is due to late and often inaccurate diagnosis and the lack of efficient therapeutics. The failure of efficient prophylaxis and therapy is based on the ability of this pathogen to activate numerous salvage pathways that are capable of overcoming the different drug-derived stresses. A major role in the protection of A. fumigatus is played by melanins. Melanins are cell wall-associated macromolecules classified as virulence determinants. The understanding of the various signaling pathways acting in this organism can be used to elucidate the mechanism beyond melanin production and help to identify ideal drug targets. (AU)

• FAPESP's process: 14/24951-7 - Identification of targets regulated by Aspergillus fumigatus phosphatase PhzA
• Grantee: Adriana Oliveira Manfiolli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/00789-6 - Functional characterization of Aspergillus nidulans phosphatases involved on glucose metabolism
• Grantee: Leandro Jose de Assis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence
• Grantee: Gustavo Henrique Goldman
• Support Opportunities: Research Projects - Thematic Grants