Abstract
Regulation of gene expression programs is crucial for the survival of microbial pathogens in host environments and for their ability to cause disease. Here we investigated the epigenetic regulator RSC (Remodels the Structure of Chromatin) in the most prevalent human fungal pathogen Candida albicans. Biochemical analysis showed that CaRSC comprises 13 subunits and contains two novel non-essential members, which we named Nri1 and Nri2 (Novel RSC Interactors) that are exclusive to the CTG clade of Saccharomycotina. Genetic analysis showed distinct essentiality of C. albicans RSC subunits compared to model fungal species suggesting functional and structural divergence of RSC functions in this fungal pathogen. Transcriptomic and proteomic profiling of a conditional mutant of the essential catalytic subunit gene STH1 demonstrated global roles of RSC in C. albicans biology, with the majority of growth-related processes affected, as well as mis-regulation of genes involved in morphotype switching, host-pathogen interaction and adaptive fitness. We further assessed the functions of non-essential CaRSC subunits, showing that the novel subunit Nri1 and the bromodomain subunit Rsc4 play roles in filamentation and stress responses; and also interacted at the genetic level to regulate cell viability. Consistent with these roles, Rsc4 is required for full virulence of C. albicans in the murine model of systemic infection. Taken together, our data builds the first comprehensive study of the composition and roles of RSC in C. albicans, showing both conserved and distinct features compared to model fungal systems. The study illuminates how C. albicans uses RSC-dependent transcriptional regulation to respond to environmental signals and drive survival fitness and virulence in mammals.
Highlights
Candida spp. account for over 400,000 cases of invasive infections per year globally [1]
The Remodels the Structure of Chromatin (RSC) complex, disrupts histone-DNA contacts and causes DNA translocation using energy derived from ATP hydrolysis
The importance of gene expression in regulating pathogenic traits has been widely recognized in the pathogenic yeast Candida albicans, the contributions of chromatin regulators in general, and the RSC complex in particular remain understudied
Summary
Candida spp. account for over 400,000 cases of invasive infections per year globally [1] Of these species, Candida albicans is the most prevalent cause of both invasive and superficial human fungal infections [1, 2]. C. albicans is challenged by hostile conditions such as immune responses, metabolic and oxidative stresses and exposure to anti-fungal drugs during therapy. To counter these stresses, C. albicans has evolved robust adaptive response mechanisms such as expression of proteins that facilitate tissue adhesion and invasion, host cell damage, acquisition and utilization of diverse carbon sources, and adaptation to various environmental assaults (reviewed in [3]). C. albicans undergoes a morphology switch from yeast to hyphal form in response to a range of external signals [4], and this transition is regarded as an important attribute of virulence since it enables tissue adhesion and invasion [5], escape from immune cells [6] and biofilm formation [7]
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