title: Sulphiredoxin plays peroxiredoxin-dependent and -independent roles via the HOG signalling pathway in Cryptococcus neoformans and contributes to fungal virulence.
abstract: Mechanisms of oxidative stress resistance are crucial virulence factors for survival and proliferation of fungal pathogens within the human host. In this study we have identified and functionally characterized the role of sulphiredoxin, Srx1, in oxidative stress resistance of Cryptococcus neoformans causing fungal meningoencephalitis and regulation of peroxiredoxins, Tsa1 and Tsa3, and thioredoxins, Trx1 and Trx2. The C. neoformans HOG (High Osmolarity Glycerol response) pathway was essential for the transcriptional regulation of SRX1 under peroxide stress conditions. A gene deletion study revealed that Srx1 was required for cells to counteract peroxide stress, but not other oxidative damaging agents. HOG1 was found to be essential for the induction of adaptive response to peroxide stress with concurrent repression of ergosterol biosynthesis in an SRX1-independent manner. Consistent with this, phosphorylation of C. neoformans Hog1 was modulated by both low and high doses of exogenous hydrogen peroxide treatment. Immunoblot analysis using the C. neoformans Tsa1 specific antibody revealed that both Srx1 and Trx1 were essential for recycling of oxidized Tsa1. In addition to its role in peroxide sensing and response C. neoformans Srx1 was also found to be required for a peroxiredoxin-independent function in promoting fungicide-dependent cell swelling and growth arrest. Finally we showed the importance of C. neoformans Srx1 in fungal pathogenesis by demonstrating its requirement for full virulence using a mouse infection model.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Upadhya
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Hyelim
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Jung
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Goun
authors.initials: G
authors.lastname: Park
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Woei
authors.initials: W
authors.lastname: Lam
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lodge
authors.affiliation: Department of Biotechnology, Center for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D003453:Cryptococcosis; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004875:Ergosterol / Q000096:biosynthesis*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005800:Genes, Fungal; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D008808:Mice, Inbred CBA; D054464:Peroxiredoxins / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000891:Anti-Infective Agents, Local; D004149:Dioxoles; D005656:Fungal Proteins; D011758:Pyrroles; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; C108339:fludioxonil; D004875:Ergosterol