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

PLoS Pathogens

Arndt von Haeseler¹  Fritz J. Sedlazeck¹  Florian Zwolanek²  Karl Kuchler²  Sabrina Jenull²  Michael Tscherner²  Andriy Petryshyn²  Ingrid E. Frohner²  Neeraj Chauhan³  John Mavrianos³ 

[1] Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Campus Vienna Biocenter, Vienna, Austria;Department for Medical Biochemistry, Medical University of Vienna, Max F. Perutz Laboratories, Campus Vienna Biocenter, Vienna, Austria;Public Health Research Institute, New Jersey Medical School - Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America

关键词: C;    ida albicans;    Histones;    Oxidative stress;    Antimicrobial resistance;    Azoles;    Mouse models;    Chromatin;    Gene regulation;   

DOI  :  10.1371/journal.ppat.1005218

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY