title: 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.
authors.affiliation: Department of Microbiology and Immunology, University at Buffalo, The State University of New York Buffalo, NY, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Panepinto
authors.affiliation: Department of Microbiology, Monash University Clayton, VIC, Australia ; Victorian Bioinformatics Consortium, School of Biomedical Sciences, Monash University Clayton, VIC, Australia.
authors.forename: Eva
authors.initials: E
authors.lastname: Heinz
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University Clayton, VIC, Australia.
authors.forename: Ana
authors.initials: A
authors.lastname: Traven
keywords: Candida albicans; Ccr4-NOT; Cryptococcus neoformans; cell wall; fungal pathogen; stress adaptation