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

John C. Panepinto,Ana Traven,Eva Heinz

doi:10.3389/fgene.2013.00302

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.

Highlights

Model fungal species, such as the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, have served as powerful genetic models for elucidating the fundamental principles of eukaryotic cellular and molecular biology
We argue that the pleiotropic functions of this complex are beneficial in the context of fungal pathogenesis in two ways: (i) by studying Ccr4-NOT, we can uncover novel mechanistic links between cellular pathways that impact on fungal virulence, and (ii) the pleiotropic functions could be beneficial for targeting the complex with antifungal molecules—inactivating Ccr4-NOT could simultaneously cripple several functions important for virulence, resulting in more efficient elimination of the pathogen
In S. cerevisiae, C. neoformans and C. albicans Ccr4-NOT has been implicated in the adaptation to nutrient, temperature and oxygen stress, suggesting this complex is a key player in adaptive response that mediate fungal growth and survival in the host

Summary

Introduction

Model fungal species, such as the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, have served as powerful genetic models for elucidating the fundamental principles of eukaryotic cellular and molecular biology. The fungal Ccr4-NOT complex has been implicated in orchestrating gene expression networks that impact on pathways key for virulence in pathogenic species.

Results

Conclusion