The DEAD-box RNA helicase Vad1 regulates multiple virulence-associated genes in Cryptococcus neoformans.

The study of fungal regulatory networks is essential to the understanding of how these pathogens respond to host environmental signals with effective virulence-associated traits. In this study, a virulence-associated DEAD-box RNA helicase-encoding gene (VAD1) was isolated from a mutant defective in the virulence factor laccase. A Deltavad1 mutant exhibited a profound reduction in virulence in a mouse model that was restored after reconstitution with WT VAD1. Loss of VAD1 resulted in upregulation of NOT1, a gene encoding a global repressor of transcription. NOT1 was found to act as an intermediary transcriptional repressor of laccase. Vad1 was located within macromolecular complexes that formed cytoplasmic granular bodies in mature cells and during infection of mouse brain. In addition, VAD1 was shown by in situ hybridization to be expressed in the brain of an AIDS patient coinfected with C. neoformans. To understand the role of VAD1 in virulence, a functional genomics approach was used to identify 3 additional virulence determinants dependent on VAD1: PCK1, TUF1, and MPF3, involved in gluconeogenesis, mitochondrial protein synthesis, and cell wall integrity, respectively. These data show that fungal virulence-associated genes are coordinately regulated and that an analysis of such transcriptomes allows for the identification of important new genes involved in the normal growth and virulence of fungal pathogens.
AuthorsJohn Panepinto, Lide Liu, Jeanie Ramos, Xudong Zhu, Tibor Valyi-Nagy, Saliha Eksi, Jianmin Fu, H Ari Jaffe, Brian Wickes, Peter R Williamson
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 3 Pg. 632-41 (Mar 2005) ISSN: 0021-9738 [Print] United States
PMID15765146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Fungal Proteins
  • Recombinant Fusion Proteins
  • Laccase
  • RNA Helicases
  • Amino Acid Motifs
  • Animals
  • Brain (cytology, microbiology)
  • Cryptococcosis
  • Cryptococcus neoformans (cytology, enzymology, genetics, pathogenicity)
  • Fungal Proteins (genetics, metabolism)
  • Gene Expression Regulation, Fungal
  • Genes, Fungal
  • Genomics
  • Humans
  • In Situ Hybridization
  • Laccase (genetics, metabolism)
  • Mice
  • Phenotype
  • RNA Helicases (genetics, metabolism)
  • Recombinant Fusion Proteins (genetics, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!

Choose Username:
Verify Password:
Enter Code Shown: