Zap1 regulates zinc homeostasis and modulates virulence in Cryptococcus gattii

PLoS One. 2012;7(8):e43773. doi: 10.1371/journal.pone.0043773. Epub 2012 Aug 20.

Abstract

Zinc homeostasis is essential for fungal growth, as this metal is a critical structural component of several proteins, including transcription factors. The fungal pathogen Cryptococcus gattii obtains zinc from the stringent zinc-limiting milieu of the host during the infection process. To characterize the zinc metabolism in C. gattii and its relationship to fungal virulence, the zinc finger protein Zap1 was functionally characterized. The C. gattii ZAP1 gene is an ortholog of the master regulatory genes zafA and ZAP1 that are found in Aspergillus fumigatus and Saccharomyces cerevisiae, respectively. There is some evidence to support an association between Zap1 and zinc metabolism in C. gattii: (i) ZAP1 expression is highly induced during zinc deprivation, (ii) ZAP1 knockouts demonstrate impaired growth in zinc-limiting conditions, (iii) Zap1 regulates the expression of ZIP zinc transporters and distinct zinc-binding proteins and (iv) Zap1 regulates the labile pool of intracellular zinc. In addition, the deletion of ZAP1 reduces C. gattii virulence in a murine model of cryptococcosis infection. Based on these observations, we postulate that proper zinc metabolism plays a crucial role in cryptococcal virulence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cryptococcosis / microbiology
  • Cryptococcus gattii / metabolism*
  • Cryptococcus gattii / pathogenicity*
  • Female
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Reactive Oxygen Species / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Virulence / genetics
  • Virulence / physiology*
  • Zinc / metabolism*

Substances

  • Fungal Proteins
  • Reactive Oxygen Species
  • Transcription Factors
  • Zinc

Grant support

This work was supported by grants from the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ –476029/2010-4), Financiadora de Estudos e Projetos (FINEP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.