Nitrogen Metabolism and Virulence of Candida Albicans Require the GATA-type Transcriptional Activator Encoded by GAT1

Mol Microbiol. 2003 Nov;50(3):993-1004. doi: 10.1046/j.1365-2958.2003.03747.x.

Abstract

Nitrogen acquisition and metabolism is central to microbial growth. A conserved family of zinc-finger containing transcriptional regulators known as GATA-factors ensures efficient utilization of available nitrogen sources by fungi. GATA factors activate expression of nitrogen catabolic pathways when preferred nitrogen sources are absent or limiting, a phenomenon known as nitrogen catabolite repression. GAT1 of Candida albicans encodes a GATA-factor homologous to the AREA protein of Aspergillus nidulans and related transcription factors involved in nitrogen regulation. Two observations implicated GAT1 in nitrogen regulation. The growth of mutants lacking GAT1 was reduced when isoleucine, tyrosine or tryptophan were the sole source of nitrogen. Secondly, when cultured on a secondary nitrogen source, gat1Delta mutants were unable to activate expression of GAP1, UGA4 or DAL5, which were shown to be nitrogen regulated in C. albicans. This regulatory defect did not prevent filamentation of gat1Delta mutants in nitrogen repressing or non-repressing conditions, demonstrating that nitrogen catabolite repression does not influence dimorphism. The mutants were, however, highly attenuated in a murine model of disseminated candidiasis. Attenuation was not associated with any diminution of growth in serum or ability to utilize serum amino acids. The results indicate an important role for nitrogen regulation in the virulence of C. albicans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Candida albicans / metabolism*
  • Candida albicans / pathogenicity*
  • Candidiasis / microbiology
  • Cell Division / physiology
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Gene Expression Regulation, Fungal
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Mutation
  • Nitrogen / metabolism*
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism
  • Sequence Homology, Amino Acid
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Virulence / physiology
  • Zinc Fingers
  • ras GTPase-Activating Proteins / genetics
  • ras GTPase-Activating Proteins / metabolism

Substances

  • AreA protein, Aspergillus nidulans
  • Fungal Proteins
  • GAT1 protein, Candida albicans
  • Organic Anion Transporters
  • Trans-Activators
  • Transcription Factors
  • ras GTPase-Activating Proteins
  • Nitrogen