title: 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.
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Tscherner
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Zwolanek
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jenull
authors.affiliation: Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Fritz J
authors.initials: FJ
authors.lastname: Sedlazeck
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Andriy
authors.initials: A
authors.lastname: Petryshyn
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Frohner
authors.affiliation: Public Health Research Institute, New Jersey Medical School - Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Mavrianos
authors.affiliation: Public Health Research Institute, New Jersey Medical School - Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Chauhan
authors.affiliation: Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Arndt
authors.initials: A
authors.lastname: von Haeseler
authors.affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kuchler
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002176:Candida albicans / Q000201:enzymology / Q000472:pathogenicity*; D002177:Candidiasis / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D014774:Virulence
chemical_list: D051548:Histone Acetyltransferases; C110880:histone acetyltransferase type B complex