title: A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans.
abstract: Cryptococcosis, caused by the basidiomycetous fungus Cryptococcus neoformans, is responsible for more than 600,000 deaths annually in AIDS patients. Flucytosine is one of the most commonly used antifungal drugs for its treatment, but its resistance and regulatory mechanisms have never been investigated at the genome scale in C. neoformans. In the present study, we performed comparative transcriptome analysis by employing two-component system mutants (tco1Δ and tco2Δ) exhibiting opposing flucytosine susceptibility. As a result, a total of 177 flucytosine-responsive genes were identified, and many of them were found to be regulated by Tco1 or Tco2. Among these, we discovered an APSES-like transcription factor, Mbs1 (Mbp1- and Swi4-like protein 1). Expression analysis revealed that MBS1 was regulated in response to flucytosine in a Tco2/Hog1-dependent manner. Supporting this, C. neoformans with the deletion of MBS1 exhibited increased susceptibility to flucytosine. Intriguingly, Mbs1 played pleiotropic roles in diverse cellular processes of C. neoformans. Mbs1 positively regulated ergosterol biosynthesis and thereby affected polyene and azole drug susceptibility. Mbs1 was also involved in genotoxic and oxidative stress responses. Furthermore, Mbs1 promoted production of melanin and capsule and thereby was required for full virulence of C. neoformans. In conclusion, Mbs1 is considered to be a novel antifungal therapeutic target for treatment of cryptococcosis.
authors.affiliation: Department of Biotechnology, Centre for Fungal Pathogenesis, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
authors.forename: Min-Hee
authors.initials: MH
authors.lastname: Song
authors.forename: Jang-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Min Su
authors.initials: MS
authors.lastname: Kim
authors.forename: Ja-Kyung
authors.initials: JK
authors.lastname: Yoon
authors.forename: Theodore C
authors.initials: TC
authors.lastname: White
authors.forename: Anna
authors.initials: A
authors.lastname: Floyd
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
authors.forename: Anna K
authors.initials: AK
authors.lastname: Strain
authors.forename: Judith N
authors.initials: JN
authors.lastname: Nielsen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D015169:Colony Count, Microbial; D017124:Conserved Sequence; D003453:Cryptococcosis / Q000276:immunology / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology; D004249:DNA Damage; D025141:Drug Resistance, Fungal; D004875:Ergosterol / Q000096:biosynthesis; D005260:Female; D005437:Flucytosine / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D055786:Gene Knockout Techniques; D058685:Genetic Pleiotropy; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D037521:Virulence Factors / Q000096:biosynthesis
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D014157:Transcription Factors; D037521:Virulence Factors; D005437:Flucytosine; D011494:Protein Kinases; D004875:Ergosterol
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