A flucytosine-responsive mbp1/swi4-like protein, mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of cryptococcus neoformans

Min Hee Song, Jang Won Lee, Min Su Kim, Ja Kyung Yoon, Theodore C. White, Anna Floyd, Joseph Heitman, Anna K. Strain, Judith N. Nielsen, Kirsten Nielsen, Yong-Sun Bahn

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 (tco1 and tco2) 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 (Mbp1and Swi4like 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.

Original languageEnglish
Pages (from-to)53-67
Number of pages15
JournalEukaryotic Cell
Volume11
Issue number1
DOIs
Publication statusPublished - 2012 Jan 1

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Fungal Drug Resistance
Flucytosine
Cryptococcus neoformans
Virulence
Cryptococcosis
Proteins
Polyenes
Ergosterol
Azoles
Melanins
Gene Expression Profiling
Pharmaceutical Preparations
DNA Damage
Capsules
Acquired Immunodeficiency Syndrome
Oxidative Stress
Fungi
Transcription Factors
Therapeutics
Genome

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

Song, Min Hee ; Lee, Jang Won ; Kim, Min Su ; Yoon, Ja Kyung ; White, Theodore C. ; Floyd, Anna ; Heitman, Joseph ; Strain, Anna K. ; Nielsen, Judith N. ; Nielsen, Kirsten ; Bahn, Yong-Sun. / A flucytosine-responsive mbp1/swi4-like protein, mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of cryptococcus neoformans. In: Eukaryotic Cell. 2012 ; Vol. 11, No. 1. pp. 53-67.
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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 (tco1 and tco2) 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 (Mbp1and Swi4like 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.",
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A flucytosine-responsive mbp1/swi4-like protein, mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of cryptococcus neoformans. / Song, Min Hee; Lee, Jang Won; Kim, Min Su; Yoon, Ja Kyung; White, Theodore C.; Floyd, Anna; Heitman, Joseph; Strain, Anna K.; Nielsen, Judith N.; Nielsen, Kirsten; Bahn, Yong-Sun.

In: Eukaryotic Cell, Vol. 11, No. 1, 01.01.2012, p. 53-67.

Research output: Contribution to journalArticle

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