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

Tscherner M, Zwolanek F, Je S, Sedlazeck FJ, Petryshyn A, Frohner IE, Mavrianos J, Chauhan N, von Haeseler A, Kuchler K - PLoS Pathog. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Specific functional gene groups are upregulated in cells lacking Hat1.(A) GO terms enriched among 2-fold significantly upregulated genes in logarithmically growing hat1Δ/Δ cells are shown. (B) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ and rtt109Δ/Δ strains only. (C) GO terms enriched within genes significantly upregulated in the hat1Δ/Δ and cac2Δ/Δ strains only. (D) The panel shows GO terms found among genes significantly upregulated in the hat1Δ/Δ mutant only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains. (E) GO terms enriched among significantly upregulated genes in hat1Δ/Δ cells after treatment with H2O2 are shown. (F) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ strain only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains upon H2O2 treatment. (A-F) The corresponding p-values for the enrichment (empty bars) and the percentage of genes changed within the GO group (filled bars) are presented. The absolute number of regulated genes within a GO group is presented in brackets. Groups containing identical genes are depicted in the same color. Significantly regulated genes were defined by a p-value <0.05.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608838&req=5

ppat.1005218.g005: Specific functional gene groups are upregulated in cells lacking Hat1.(A) GO terms enriched among 2-fold significantly upregulated genes in logarithmically growing hat1Δ/Δ cells are shown. (B) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ and rtt109Δ/Δ strains only. (C) GO terms enriched within genes significantly upregulated in the hat1Δ/Δ and cac2Δ/Δ strains only. (D) The panel shows GO terms found among genes significantly upregulated in the hat1Δ/Δ mutant only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains. (E) GO terms enriched among significantly upregulated genes in hat1Δ/Δ cells after treatment with H2O2 are shown. (F) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ strain only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains upon H2O2 treatment. (A-F) The corresponding p-values for the enrichment (empty bars) and the percentage of genes changed within the GO group (filled bars) are presented. The absolute number of regulated genes within a GO group is presented in brackets. Groups containing identical genes are depicted in the same color. Significantly regulated genes were defined by a p-value <0.05.

Mentions: To further characterize genes upregulated upon loss of Hat1, we performed a GO term enrichment analysis. Without H2O2 treatment, at least 2-fold upregulated genes in the hat1Δ/Δ mutant were strongly enriched for genes involved in lipid catabolic processes and oxidation-reduction processes (Fig 5A). Interestingly, the latter group includes genes encoding for proteins with functions in oxidative stress tolerance like the catalase (CAT1), superoxide dismutases (SOD3-6) and a thiol peroxidase (orf19.87) [26,54–56]. Preliminary proteomics data also identified this group of proteins as being upregulated in the hat1Δ/Δ mutant (S2C Fig). Of note, we failed to observe enrichment for DNA damage response genes most likely due to the fact that Hat1 is involved in different processes in C. albicans. This leads to a high number of differentially expressed genes in the mutant and could hamper detection of enriched GO groups. Therefore, we analyzed subsets of differentially expressed genes based on their expression in the three mutants. As expected, due to their DNA damage phenotype, genes significantly upregulated only in the hat1Δ/Δ and the rtt109Δ/Δ mutants were strongly enriched for DNA damage repair genes (Fig 5B). The specific overlap of regulated genes between hat1Δ/Δ and cac2Δ/Δ was still enriched for genes involved in oxidation-reduction processes and arginine metabolism, implying that Hat1 and Cac2 might be involved in the same processes (Fig 5C). Finally, we identified genes involved in mitochondrial degradation and microautophagy which were significantly upregulated only in the hat1Δ/Δ mutant (Fig 5D).


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

Tscherner M, Zwolanek F, Je S, Sedlazeck FJ, Petryshyn A, Frohner IE, Mavrianos J, Chauhan N, von Haeseler A, Kuchler K - PLoS Pathog. (2015)

Specific functional gene groups are upregulated in cells lacking Hat1.(A) GO terms enriched among 2-fold significantly upregulated genes in logarithmically growing hat1Δ/Δ cells are shown. (B) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ and rtt109Δ/Δ strains only. (C) GO terms enriched within genes significantly upregulated in the hat1Δ/Δ and cac2Δ/Δ strains only. (D) The panel shows GO terms found among genes significantly upregulated in the hat1Δ/Δ mutant only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains. (E) GO terms enriched among significantly upregulated genes in hat1Δ/Δ cells after treatment with H2O2 are shown. (F) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ strain only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains upon H2O2 treatment. (A-F) The corresponding p-values for the enrichment (empty bars) and the percentage of genes changed within the GO group (filled bars) are presented. The absolute number of regulated genes within a GO group is presented in brackets. Groups containing identical genes are depicted in the same color. Significantly regulated genes were defined by a p-value <0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608838&req=5

ppat.1005218.g005: Specific functional gene groups are upregulated in cells lacking Hat1.(A) GO terms enriched among 2-fold significantly upregulated genes in logarithmically growing hat1Δ/Δ cells are shown. (B) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ and rtt109Δ/Δ strains only. (C) GO terms enriched within genes significantly upregulated in the hat1Δ/Δ and cac2Δ/Δ strains only. (D) The panel shows GO terms found among genes significantly upregulated in the hat1Δ/Δ mutant only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains. (E) GO terms enriched among significantly upregulated genes in hat1Δ/Δ cells after treatment with H2O2 are shown. (F) The plot shows GO terms found within genes significantly upregulated in the hat1Δ/Δ strain only and not in the rtt109Δ/Δ and the cac2Δ/Δ strains upon H2O2 treatment. (A-F) The corresponding p-values for the enrichment (empty bars) and the percentage of genes changed within the GO group (filled bars) are presented. The absolute number of regulated genes within a GO group is presented in brackets. Groups containing identical genes are depicted in the same color. Significantly regulated genes were defined by a p-value <0.05.
Mentions: To further characterize genes upregulated upon loss of Hat1, we performed a GO term enrichment analysis. Without H2O2 treatment, at least 2-fold upregulated genes in the hat1Δ/Δ mutant were strongly enriched for genes involved in lipid catabolic processes and oxidation-reduction processes (Fig 5A). Interestingly, the latter group includes genes encoding for proteins with functions in oxidative stress tolerance like the catalase (CAT1), superoxide dismutases (SOD3-6) and a thiol peroxidase (orf19.87) [26,54–56]. Preliminary proteomics data also identified this group of proteins as being upregulated in the hat1Δ/Δ mutant (S2C Fig). Of note, we failed to observe enrichment for DNA damage response genes most likely due to the fact that Hat1 is involved in different processes in C. albicans. This leads to a high number of differentially expressed genes in the mutant and could hamper detection of enriched GO groups. Therefore, we analyzed subsets of differentially expressed genes based on their expression in the three mutants. As expected, due to their DNA damage phenotype, genes significantly upregulated only in the hat1Δ/Δ and the rtt109Δ/Δ mutants were strongly enriched for DNA damage repair genes (Fig 5B). The specific overlap of regulated genes between hat1Δ/Δ and cac2Δ/Δ was still enriched for genes involved in oxidation-reduction processes and arginine metabolism, implying that Hat1 and Cac2 might be involved in the same processes (Fig 5C). Finally, we identified genes involved in mitochondrial degradation and microautophagy which were significantly upregulated only in the hat1Δ/Δ mutant (Fig 5D).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus