Abstract
Fungal virulence is regulated by a tight interplay of transcriptional control and chromatin remodelling. Despite compelling evidence that lysine acetylation modulates virulence of pathogenic fungi such as Candida albicans, the underlying mechanisms have remained largely unexplored. We report here that Gcn5, a paradigm lysyl-acetyl transferase (KAT) modifying both histone and non-histone targets, controls fungal morphogenesis – a key virulence factor of C. albicans. Our data show that genetic removal of GCN5 abrogates fungal virulence in mice, suggesting strongly diminished fungal fitness in vivo. This may at least in part arise from increased susceptibility to killing by macrophages, as well as by other phagocytes such as neutrophils or monocytes. Loss of GCN5 also causes hypersensitivity to the fungicidal drug caspofungin. Caspofungin hypersusceptibility requires the master regulator Efg1, working in concert with Gcn5. Moreover, Gcn5 regulates multiple independent pathways, including adhesion, cell wall-mediated MAP kinase signaling, hypersensitivity to host-derived oxidative stress, and regulation of the Fks1 glucan synthase, all of which play critical roles in virulence and antifungal susceptibility. Hence, Gcn5 regulates fungal virulence through multiple mechanisms, suggesting that specific inhibition of Gcn5 could offer new therapeutic strategies to combat invasive fungal infections.
Highlights
Invasive fungal infections claim about 1.5 million lives each year[1]
Most if not all fungal virulence traits are tightly controlled by a dual-layer network that engages transcriptional regulatory networks, whose activity is modulated by specific histone modification enzymes that alter chromatin states
We asked if the type A KAT, Gcn[5], is involved in fungal morphogenesis
Summary
Invasive fungal infections claim about 1.5 million lives each year[1]. Candida species (spp) rank among the top three for four causes of nosocomial infectious diseases[2,3]. Yeast Gcn[5] is part of large transcriptional multiprotein complexes, including SAGA (Spt-Ada-Gcn[5] acetyltransferase), ADA (Ada2-Gcn5-Ada3), HAT-A2 and SLIK (SAGA-like) These evolutionary conserved regulatory complexes recruit the basal transcription machinery and coactivators to specific promoters, control chromatin modification and nucleosome remodelling, as well as retrograde signaling[44,45,46,47]. Candida albicans Gcn[5] attenuates pathogenicity and affects morphogenesis[56], but the mechanisms of Gcn5-mediated gene regulation, and more importantly, how Gcn[5] controls fungal pathogenicity remains largely unknown. We show that Gcn[5] controls C. albicans invasive infections by acting downstream of multiple signaling pathways that control cell wall architecture and surface remodeling. The data establish Gcn[5] as drug target which may be suitable for interfering with invasive fungal infections
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
