Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus

Author(s):Show less -

de Castro, Patricia Alves ^[1] ; Valero, Clara ^[1] ; Chiaratto, Jessica ^[1] ; Colabardini, Ana Cristina ^{[1, 2]} ; Pardeshi, Lakhansing ^{[2, 3]} ; Silva, Lilian Pereira ^[1] ; Almeida, Fausto ^[4] ; Rocha, Marina Campos ^[5] ; Silva, Roberto Nascimento ^[4] ; Malavazi, Iran ^[5] ; Du, Wenyue ^[6] ; Dyer, Paul S. ^[6] ; Brock, Matthias ^[6] ; Loures, Flavio Vieira ^[7] ; Wong, Koon Ho ^{[2, 8]} ; Goldman, Gustavo H. ^[1]

Affiliation

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

^[2] Univ Macau, Fac Hlth Sci, Taipa, Macao - Peoples R China

^[3] Univ Macau, Fac Hlth Sci, Genom & Bioinformat Core, Taipa, Macao - Peoples R China

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Ribeirao Preto - Brazil

^[5] Univ Fed Sao Carlos, Ctr Ciencias Biol & Saude, Dept Genet & Evolucao, Sao Carlos, SP - Brazil

^[6] Univ Nottingham, Sch Life Sci, Fungal Genet & Biol Grp, Nottingham - England

^[7] Univ Fed Sao Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos - Brazil

^[8] Univ Macau, Fac Hlth Sci, Inst Translat Med, Taipa, Macao - Peoples R China

• Document type: Journal article
• Source: MBIO; v. 12, n. 1 JAN-FEB 2021.
• Web of Science Citations: 0

Abstract

The fungal zinc finger transcription factor NsdC is named after, and is best known for, its essential role in sexual reproduction (never in sexual development). In previous studies with Aspergillus nidulans, it was also shown to have roles in promotion of vegetative growth and suppression of asexual conidiation. In this study, the function of the nsdC homologue in the opportunistic human pathogen A. fumigatus was investigated. NsdC was again found to be essential for sexual development, with deletion of the nsdC gene in both MAT1-1 and MAT1-2 mating partners of a cross leading to complete loss of fertility. However, a functional copy of nsdC in one mating partner was sufficient to allow sexual reproduction. Deletion of nsdC also led to decreased vegetative growth and allowed conidiation in liquid cultures, again consistent with previous findings. However, NsdC in A. fumigatus was shown to have additional biological functions including response to calcium stress, correct organization of cell wall structure, and response to the cell wall stressors. Furthermore, virulence and host immune recognition were affected. Gene expression studies involving chromatin immunoprecipitation (ChIP) of RNA polymerase II (PolII) coupled to next-generation sequencing (Seq) revealed that deletion of nsdC resulted in changes in expression of over 620 genes under basal growth conditions. This demonstrated that this transcription factor mediates the activity of a wide variety of signaling and metabolic pathways and indicates that despite the naming of the gene, the promotion of sexual reproduction is just one among multiple roles of NsdC. IMPORTANCE Aspergillus fumigatus is an opportunistic human fungal pathogen and the main causal agent of invasive aspergillosis, a life-threatening infection especially in immunocompromised patients. A. fumigatus can undergo both asexual and sexual reproductive cycles, and the regulation of both cycles involves several genes and pathways. Here, we have characterized one of these genetic determinants, the NsdC transcription factor, which was initially identified in a screen of transcription factor null mutants showing sensitivity when exposed to high concentrations of calcium. In addition to its known essential roles in sexual reproduction and control of growth rate and asexual reproduction, we have shown in the present study that A. fumigatus NsdC transcription factor has additional previously unrecognized biological functions including calcium tolerance, cell wall stress response, and correct cell wall organization and functions in virulence and host immune recognition. Our results indicate that NsdC can play novel additional biological functions not directly related to its role played during sexual and asexual processes. (AU)

• 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
• FAPESP's process: 18/00715-3 - Molecular characterization of Aspergillus fumigatus transcription factors involved in calcium metabolism.
• Grantee: Clara Isabel Valero Fernández
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/21392-2 - "Characterization of transcription factors that have the basic domain" zipper "leucine (bZIP) ATF1 in Aspergillus fumigatus"
• Grantee: Lilian Pereira Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/07536-4 - Molecular Mechanisms Involved in Paradoxal Growth Induced by Caspofungin in Aspergillus fumigatus
• Grantee: Ana Cristina Colabardini
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/22062-6 - Molecular characterization of htlA and fhdA transcription factors of human pathogenic fungus Aspergillus fumigatus
• Grantee: Jéssica Chiaratto
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 16/12948-7 - The role of mitogen-activated protein kinase (MPKA) MpkA in regulating gliotoxin production in Aspergillus fumigatus.
• Grantee: Patrícia Alves de Castro Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/10097-8 - Multi-User Equipment approved in grant 2018/14762-3: flow cytometer FACS lyric
• Grantee: Flávio Vieira Loures
• Support Opportunities: Multi-user Equipment Program