The cellular roles of Ccr4-NOT in model and pathogenic fungi—implications for fungal virulence

Abstract

The fungal Ccr4-NOT complex has been implicated in orchestrating gene expression networks that impact on pathways key for virulence in pathogenic species. The activity of Ccr4-NOT regulates cell wall integrity, antifungal drug susceptibility, adaptation to host temperature, and the developmental switches that enable the formation of pathogenic structures, such as filamentous hyphae. Moreover, Ccr4-NOT impacts on DNA repair pathways and genome stability, opening the possibility that this gene regulator could control adaptive responses in pathogens that are driven by chromosomal alterations. Here we provide a synthesis of the cellular roles of the fungal Ccr4-NOT, focusing on pathways important for virulence toward animals. Our review is based on studies in models yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and two species that cause serious human infections, Candida albicans and Cryptococcus neoformans. We hypothesize that the activity of Ccr4-NOT could be targeted for future antifungal drug discovery, a proposition supported by the fact that inactivation of the genes encoding subunits of Ccr4-NOT in C. albicans and C. neoformans reduces virulence in the mouse infection model. We performed bioinformatics analysis to identify similarities and differences between Ccr4-NOT subunits in fungi and animals, and discuss this knowledge in the context of future antifungal strategies.

PAT-seq: a method to study the integration of 3′-UTR dynamics with gene expression in the eukaryotic transcriptome

“…S1c). Failure to appropriately silence these loci in rich media may explain the diverse phenotypes that have been assembled for this mutant (Panepinto et al 2013). …”

Multifunctional roles of the mammalian CCR4–NOT complex in physiological phenomena

“…The CCR4–NOT complex is also implicated in the regulation of cell wall integrity, antifungal drug susceptibility, and developmental switches in pathogenic fungi (Panepinto et al, 2013). As we describe here, recent studies using cultured mammalian cells and genetically modified mice have revealed distinct roles of each subunit in wide-ranging physiological phenomena.…”

Post‐transcriptional gene regulation in the biology and virulence ofCandida albicans

“…cerevisiae (Moriya and Isono, ; Kaeberlein and Guarente, ; Dagley et al ., ; Braun et al ., ), reviewed in Panepinto et al . (). Consistent with a metabolic reason, in the C .…”

“…It is unclear why the mRNA decay mutants display filamentation defects. Functions important for hyphal growth, such as cell wall biogenesis, nutrient responses and mitochondrial activity, are compromised in mRNA decay mutants in C. albicans and/or S. cerevisiae (Moriya and Isono, 1999;Kaeberlein and Guarente, 2002;Dagley et al, 2011;Braun et al, 2014), reviewed in Panepinto et al (2013). Consistent with a metabolic reason, in the C. albicans xrn1 mutant protein levels for several metabolic enzymes are distinct from wild type cells, and overexpression of the pyruvate dehydrogenase subunit Lpd1 rescued hyphal defects (Lee et al, 2010).…”