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Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.

Publication ,  Journal Article
Garcia-Santamarina, S; Festa, RA; Smith, AD; Yu, C-H; Probst, C; Ding, C; Homer, CM; Yin, J; Noonan, JP; Madhani, H; Perfect, JR; Thiele, DJ
Published in: Mol Microbiol
June 2018

The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu-detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections.

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Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

June 2018

Volume

108

Issue

5

Start / End Page

473 / 494

Location

England

Related Subject Headings

  • Virulence
  • Transcription Factors
  • RNA, Fungal
  • Microbiology
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation, Fungal
  • Gene Expression Profiling
  • Fungal Proteins
  • Cryptococcus neoformans
 

Citation

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Garcia-Santamarina, S., Festa, R. A., Smith, A. D., Yu, C.-H., Probst, C., Ding, C., … Thiele, D. J. (2018). Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans. Mol Microbiol, 108(5), 473–494. https://doi.org/10.1111/mmi.13960
Garcia-Santamarina, Sarela, Richard A. Festa, Aaron D. Smith, Chen-Hsin Yu, Corinna Probst, Chen Ding, Christina M. Homer, et al. “Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.Mol Microbiol 108, no. 5 (June 2018): 473–94. https://doi.org/10.1111/mmi.13960.
Garcia-Santamarina S, Festa RA, Smith AD, Yu C-H, Probst C, Ding C, et al. Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans. Mol Microbiol. 2018 Jun;108(5):473–94.
Garcia-Santamarina, Sarela, et al. “Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans.Mol Microbiol, vol. 108, no. 5, June 2018, pp. 473–94. Pubmed, doi:10.1111/mmi.13960.
Garcia-Santamarina S, Festa RA, Smith AD, Yu C-H, Probst C, Ding C, Homer CM, Yin J, Noonan JP, Madhani H, Perfect JR, Thiele DJ. Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans. Mol Microbiol. 2018 Jun;108(5):473–494.
Journal cover image

Published In

Mol Microbiol

DOI

EISSN

1365-2958

Publication Date

June 2018

Volume

108

Issue

5

Start / End Page

473 / 494

Location

England

Related Subject Headings

  • Virulence
  • Transcription Factors
  • RNA, Fungal
  • Microbiology
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation, Fungal
  • Gene Expression Profiling
  • Fungal Proteins
  • Cryptococcus neoformans