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Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition.

Publication ,  Journal Article
Liu, N-N; Flanagan, PR; Zeng, J; Jani, NM; Cardenas, ME; Moran, GP; Köhler, JR
Published in: Proc Natl Acad Sci U S A
June 13, 2017

The Target of Rapamycin (TOR) pathway regulates morphogenesis and responses to host cells in the fungal pathogen Candida albicans Eukaryotic Target of Rapamycin complex 1 (TORC1) induces growth and proliferation in response to nitrogen and carbon source availability. Our unbiased genetic approach seeking unknown components of TORC1 signaling in C. albicans revealed that the phosphate transporter Pho84 is required for normal TORC1 activity. We found that mutants in PHO84 are hypersensitive to rapamycin and in response to phosphate feeding, generate less phosphorylated ribosomal protein S6 (P-S6) than the WT. The small GTPase Gtr1, a component of the TORC1-activating EGO complex, links Pho84 to TORC1. Mutants in Gtr1 but not in another TORC1-activating GTPase, Rhb1, are defective in the P-S6 response to phosphate. Overexpression of Gtr1 and a constitutively active Gtr1Q67L mutant suppresses TORC1-related defects. In Saccharomyces cerevisiae pho84 mutants, constitutively active Gtr1 suppresses a TORC1 signaling defect but does not rescue rapamycin hypersensitivity. Hence, connections from phosphate homeostasis (PHO) to TORC1 may differ between C. albicans and S. cerevisiae The converse direction of signaling from TORC1 to the PHO regulon previously observed in S. cerevisiae was genetically shown in C. albicans using conditional TOR1 alleles. A small molecule inhibitor of Pho84, a Food and Drug Administration-approved drug, inhibits TORC1 signaling and potentiates the activity of the antifungals amphotericin B and micafungin. Anabolic TORC1-dependent processes require significant amounts of phosphate. Our study shows that phosphate availability is monitored and also controlled by TORC1 and that TORC1 can be indirectly targeted by inhibiting Pho84.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 13, 2017

Volume

114

Issue

24

Start / End Page

6346 / 6351

Location

United States

Related Subject Headings

  • Signal Transduction
  • Saccharomyces cerevisiae Proteins
  • Regulon
  • Proton-Phosphate Symporters
  • Phosphates
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Models, Biological
  • Mechanistic Target of Rapamycin Complex 1
  • Hyphae
 

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Liu, N.-N., Flanagan, P. R., Zeng, J., Jani, N. M., Cardenas, M. E., Moran, G. P., & Köhler, J. R. (2017). Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. Proc Natl Acad Sci U S A, 114(24), 6346–6351. https://doi.org/10.1073/pnas.1617799114
Liu, Ning-Ning, Peter R. Flanagan, Jumei Zeng, Niketa M. Jani, Maria E. Cardenas, Gary P. Moran, and Julia R. Köhler. “Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition.Proc Natl Acad Sci U S A 114, no. 24 (June 13, 2017): 6346–51. https://doi.org/10.1073/pnas.1617799114.
Liu N-N, Flanagan PR, Zeng J, Jani NM, Cardenas ME, Moran GP, et al. Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. Proc Natl Acad Sci U S A. 2017 Jun 13;114(24):6346–51.
Liu, Ning-Ning, et al. “Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition.Proc Natl Acad Sci U S A, vol. 114, no. 24, June 2017, pp. 6346–51. Pubmed, doi:10.1073/pnas.1617799114.
Liu N-N, Flanagan PR, Zeng J, Jani NM, Cardenas ME, Moran GP, Köhler JR. Phosphate is the third nutrient monitored by TOR in Candida albicans and provides a target for fungal-specific indirect TOR inhibition. Proc Natl Acad Sci U S A. 2017 Jun 13;114(24):6346–6351.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 13, 2017

Volume

114

Issue

24

Start / End Page

6346 / 6351

Location

United States

Related Subject Headings

  • Signal Transduction
  • Saccharomyces cerevisiae Proteins
  • Regulon
  • Proton-Phosphate Symporters
  • Phosphates
  • Mutation
  • Monomeric GTP-Binding Proteins
  • Models, Biological
  • Mechanistic Target of Rapamycin Complex 1
  • Hyphae