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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.

Publication ,  Journal Article
Song, M-H; Lee, J-W; Kim, MS; Yoon, J-K; White, TC; Floyd, A; Heitman, J; Strain, AK; Nielsen, JN; Nielsen, K; Bahn, Y-S
Published in: Eukaryot Cell
January 2012

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.

Duke Scholars

Published In

Eukaryot Cell

DOI

EISSN

1535-9786

Publication Date

January 2012

Volume

11

Issue

1

Start / End Page

53 / 67

Location

United States

Related Subject Headings

  • Virulence Factors
  • Virulence
  • Transcription Factors
  • Protein Kinases
  • Phosphorylation
  • Oxidative Stress
  • Oligonucleotide Array Sequence Analysis
  • Molecular Sequence Data
  • Microbiology
  • Microbial Viability
 

Citation

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Song, M.-H., Lee, J.-W., Kim, M. S., Yoon, J.-K., White, T. C., Floyd, A., … Bahn, Y.-S. (2012). A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans. Eukaryot Cell, 11(1), 53–67. https://doi.org/10.1128/EC.05236-11
Song, Min-Hee, Jang-Won Lee, Min Su Kim, Ja-Kyung Yoon, Theodore C. White, Anna Floyd, Joseph Heitman, et al. “A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans.Eukaryot Cell 11, no. 1 (January 2012): 53–67. https://doi.org/10.1128/EC.05236-11.
Song, Min-Hee, et al. “A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans.Eukaryot Cell, vol. 11, no. 1, Jan. 2012, pp. 53–67. Pubmed, doi:10.1128/EC.05236-11.
Song M-H, Lee J-W, Kim MS, Yoon J-K, White TC, Floyd A, Heitman J, Strain AK, Nielsen JN, Nielsen K, Bahn Y-S. A flucytosine-responsive Mbp1/Swi4-like protein, Mbs1, plays pleiotropic roles in antifungal drug resistance, stress response, and virulence of Cryptococcus neoformans. Eukaryot Cell. 2012 Jan;11(1):53–67.

Published In

Eukaryot Cell

DOI

EISSN

1535-9786

Publication Date

January 2012

Volume

11

Issue

1

Start / End Page

53 / 67

Location

United States

Related Subject Headings

  • Virulence Factors
  • Virulence
  • Transcription Factors
  • Protein Kinases
  • Phosphorylation
  • Oxidative Stress
  • Oligonucleotide Array Sequence Analysis
  • Molecular Sequence Data
  • Microbiology
  • Microbial Viability