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


PANEPINTO J., LIU L., RAMOS J., ZHU X., VALYI-NAGY T., Eksi S. , ...Daha Fazla

JOURNAL OF CLINICAL INVESTIGATION, cilt.115, sa.3, ss.632-641, 2005 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 115 Konu: 3
  • Basım Tarihi: 2005
  • Doi Numarası: 10.1172/jci200523048
  • Dergi Adı: JOURNAL OF CLINICAL INVESTIGATION
  • Sayfa Sayıları: ss.632-641

Özet

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.