title: Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans.
abstract: Thermotolerance is a crucial virulence attribute for human pathogens, including the fungus Cryptococcus neoformans that causes fatal meningitis in humans. Loss of the protein kinase Sch9 increases C. neoformans thermotolerance, but its regulatory mechanism has remained unknown. Here, we studied the Sch9-dependent and Sch9-independent signaling networks modulating C. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. During temperature upshift, genes encoding for molecular chaperones and heat shock proteins were upregulated, whereas those for translation, transcription, and sterol biosynthesis were highly suppressed. In this process, Sch9 regulated basal expression levels or induced/repressed expression levels of some temperature-responsive genes, including heat shock transcription factor (HSF1) and heat shock proteins (HSP104 and SSA1). Notably, we found that the HSF1 transcript abundance decreased but the Hsf1 protein became transiently phosphorylated during temperature upshift. Nevertheless, Hsf1 is essential for growth and its overexpression promoted C. neoformans thermotolerance. Transcriptome analysis using an HSF1 overexpressing strain revealed a dual role of Hsf1 in the oxidative stress response and thermotolerance. Chromatin immunoprecipitation demonstrated that Hsf1 binds to the step-type like heat shock element (HSE) of its target genes more efficiently than to the perfect- or gap-type HSE. This study provides insight into the thermotolerance of C. neoformans by elucidating the regulatory mechanisms of Sch9 and Hsf1 through the genome-scale identification of temperature-dependent genes.
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Dong-Hoon
authors.identifier: 0000-0002-2902-8627
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Kwang-Woo
authors.identifier: 0000-0003-0021-5100
authors.initials: KW
authors.lastname: Jung
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Soohyun
authors.identifier: 0000-0001-9563-7204
authors.initials: S
authors.lastname: Bang
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Jang-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Song
authors.affiliation: Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Anna
authors.identifier: 0000-0002-5877-0812
authors.initials: A
authors.lastname: Floyd-Averette
authors.affiliation: Departments of Pharmacology and Cancer Biology and Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Festa
authors.affiliation: Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Giuseppe
authors.identifier: 0000-0002-3278-8678
authors.initials: G
authors.lastname: Ianiri
authors.affiliation: School of BioSciences, University of Melbourne, Victoria 3010, Australia.
authors.forename: Alexander
authors.identifier: 0000-0001-5995-7040
authors.initials: A
authors.lastname: Idnurm
authors.affiliation: Departments of Pharmacology and Cancer Biology and Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Dennis J
authors.identifier: 0000-0001-7549-0145
authors.initials: DJ
authors.lastname: Thiele
authors.affiliation: Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.affiliation: Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea ysbahn@yonsei.ac.kr.
authors.forename: Yong-Sun
authors.identifier: 0000-0001-9573-5752
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013696:Temperature; D000071436:Thermotolerance / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors
keywords: Cryptococcus neoformans; Hsf1; Sch9; high temperature; transcriptome analysis