The Candida albicans Histone Acetyltransferase Hat1 Regulates Stress Resistance and Virulence via Distinct Chromatin Assembly Pathways

Abstract

Human fungal pathogens like Candida albicans respond to host immune surveillance by rapidly adapting their transcriptional programs. Chromatin assembly factors are involved in the regulation of stress genes by modulating the histone density at these loci. Here, we report a novel role for the chromatin assembly-associated histone acetyltransferase complex NuB4 in regulating oxidative stress resistance, antifungal drug tolerance and virulence in C. albicans. Strikingly, depletion of the NuB4 catalytic subunit, the histone acetyltransferase Hat1, markedly increases resistance to oxidative stress and tolerance to azole antifungals. Hydrogen peroxide resistance in cells lacking Hat1 results from higher induction rates of oxidative stress gene expression, accompanied by reduced histone density as well as subsequent increased RNA polymerase recruitment. Furthermore, hat1Δ/Δ cells, despite showing growth defects in vitro, display reduced susceptibility to reactive oxygen-mediated killing by innate immune cells. Thus, clearance from infected mice is delayed although cells lacking Hat1 are severely compromised in killing the host. Interestingly, increased oxidative stress resistance and azole tolerance are phenocopied by the loss of histone chaperone complexes CAF-1 and HIR, respectively, suggesting a central role for NuB4 in the delivery of histones destined for chromatin assembly via distinct pathways. Remarkably, the oxidative stress phenotype of hat1Δ/Δ cells is a species-specific trait only found in C. albicans and members of the CTG clade. The reduced azole susceptibility appears to be conserved in a wider range of fungi. Thus, our work demonstrates how highly conserved chromatin assembly pathways can acquire new functions in pathogenic fungi during coevolution with the host.

Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs?

“…Of course, potential risks exist as well, because drug-mediated KDAC/KAT modulation may also lead to hyper-virulence phenotypes. For instance, blocking fungal KATs/KDACs can debilitate drug resistance but could otherwise lead to hypervirulence, owing to fitness gain in vivo due to inefficient recognition by immune surveillance [38]. Of note, virulence data on the role of other important chromatin or histone regulators mediating reversible phosphorylation and/or methylation of histones are unavailable for most fungal pathogens (Table 1).…”

“…albicans [37]. Interestingly, KATs also play important roles in the morphogenetic yeast to hyphae transition [28, 29], biofilm formation, and drug resistance [38–40], as well as virulence [38]. Likewise, genetic ablation of Gcn5, a highly conserved pleiotropic fungal KAT, strongly debilitates virulence [41].…”

Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains

“…Of these, SOD5 is the most abundantly expressed in numerous models of candidiasis (60)(61)(62)(63)(64)(65) and contributes to virulence in a mouse model of disseminated candidiasis (58). The enzyme is induced during the transition to the hyphal filamentous form required for host invasion (58,66) and protects C. albicans from the superoxide burst of macrophages and neutrophils (63,(67)(68)(69). For many years, SOD5 was described as a bimetallic Cu/Zn-SOD (58,66).…”

A synthetic system that senses Candida albicans and inhibits virulence factors

“…RNA extraction, DNAse treatment 529 and qPCR analysis was done as described previously 50 . PAT1 and RIP1 reference genes 530 were used for normalization 51 . 531…”