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The DEAD-box RNA helicase Vad1 regulates multiple virulence-associated genes in Cryptococcus neoformans
John Panepinto, … , Brian Wickes, Peter R. Williamson
John Panepinto, … , Brian Wickes, Peter R. Williamson
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):632-641. https://doi.org/10.1172/JCI23048.
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Article Infectious disease Article has an altmetric score of 1

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

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Abstract

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 Δvad1 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.

Authors

John Panepinto, Lide Liu, Jeanie Ramos, Xudong Zhu, Tibor Valyi-Nagy, Saliha Eksi, Jianmin Fu, H. Ari Jaffe, Brian Wickes, Peter R. Williamson

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Figure 5

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Increased abundance of NOT1 mRNA, due to deletion of VAD1 or constitutiv...
Increased abundance of NOT1 mRNA, due to deletion of VAD1 or constitutive overexpression of NOT1, represses laccase expression. (A) Northern blot analysis of RNA from the indicated cells incubated for 3 hours in asparagine media with or without glucose. (B) Top panel: cells of the WT or the Δvad1 mutant transformed with the NOT1 RNAi construct or control plasmid incubated for 8 hours on norepinephrine agar. Bottom panel: Northern blot demonstrating NOT1 mRNA abundance in the WT strain and the Δvad1 mutant transformed with either the NOT1 RNAi construct or the control plasmid. Actin hybridization is included as a loading control. (C) Top panels: Northern analysis of WT- and NOT1-overexpressing strain (NO20) incubated for 3 hours in asparagine media without glucose, probed with NOT1 (left panel) and LAC1 (right panel). Bottom panel: The WT-, Δvad1 mutant–, and NOT1-overexpressing strain incubated on norepinephrine agar.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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