The Iron-Dependent Regulation of the Candida albicans Oxidative Stress Response by the CCAAT-Binding Factor

Chakravarti, Ananya; Camp, Kyle; McNabb, David S.; Pinto, Inês Mendes

doi:10.1371/journal.pone.0170649

Cited by 15 publications

(14 citation statements)

References 69 publications

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“…A characteristic histone fold domain (HFD) is commonly recognized as the structural marker for all Hap3 homologs, and structurally, this motif is composed of a long central α-helix flanked by two smaller α-helices and is dimerized through the extensive hydrophobic contact in a head-to-tail assembly mode (Arents et al, 1991; Gnesutta et al, 2013; Hortschansky et al, 2017). The C. albicans Hap3 contains two distinct homologs, namely Hap31 and Hap32, and studies have shown that Hap31 and Hap32 individually interact with Hap2 and Hap5 to form DNA-binding complexes under different iron conditions (Singh et al, 2011; Chakravarti et al, 2017).…”

Section: Architecture Of the Hap Complexmentioning

confidence: 99%

“…Studies have shown that the Hap complex is one of the major redox sensors for yeast cells and a member of the fine-tuning mechanism that adapts to different levels of oxidative stress (Thön et al, 2007; Chevtzoff et al, 2010; Marinho et al, 2014). For example, the subunits Hap2, Hap31/32, and Hap5 in C. albicans were found to be actively involved in regulating the expression of oxidative stress genes (e.g., CAT1 , SOD4 , GRX5 , and TRX1 ) in response to iron availability (Chakravarti et al, 2017).…”

Section: Gene Regulation Of Hap Complex In Yeastsmentioning

confidence: 99%

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The Hap Complex in Yeasts: Structure, Assembly Mode, and Gene Regulation

Mao

Chen

2019

Front. Microbiol.

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The CCAAT box-harboring proteins represent a family of heterotrimeric transcription factors which is highly conserved in eukaryotes. In fungi, one of the particularly important homologs of this family is the Hap complex that separates the DNA-binding domain from the activation domain and imposes essential impacts on regulation of a wide range of cellular functions. So far, a comprehensive summary of this complex has been described in filamentous fungi but not in the yeast. In this review, we summarize a number of studies related to the structure and assembly mode of the Hap complex in a list of representative yeasts. Furthermore, we emphasize recent advances in understanding the regulatory functions of this complex, with a special focus on its role in regulating respiration, production of reactive oxygen species (ROS) and iron homeostasis.

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Section: Architecture Of the Hap Complexmentioning

confidence: 99%

Section: Gene Regulation Of Hap Complex In Yeastsmentioning

confidence: 99%

The Hap Complex in Yeasts: Structure, Assembly Mode, and Gene Regulation

Mao

Chen

2019

Front. Microbiol.

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“…4D). Taken together, removal of GCN5 differentially regulates genes involved in oxido-reduction, ABC and MFS drug transporters, filamentation regulators, MAPK signaling modules, as well as iron / zinc homeostasis and heme acquisition, which requires Rbt5 and affects cell wall architecture by regulating its proteome including adhesins 70–74 .…”

Section: Resultsmentioning

confidence: 99%

“…glabrata 96 . Interestingly, iron homeostasis is tightly linked to cell wall architecture, and Gcn5 regulates expression of Rbt5 that affects cell wall architecture by regulating adhesins and the entire surface proteome 70–74 . In addition, Gcn5 selectively controls hyphal regulator genes such as EFG1 , TEC1 , but also hyphal genes, including HWP1 and ECE1 .…”

Section: Discussionmentioning

confidence: 99%

The Fungal Histone Acetyl Transferase Gcn5 Controls Virulence of the Human Pathogen Candida albicans through Multiple Pathways

Shivarathri

Tscherner

Zwolanek

et al. 2019

Sci Rep

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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.

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“…Hap43 in turn represses iron consuming processes and induces iron uptake genes (Baek et al, 2008 ; Singh et al, 2011 ). Interestingly, the CCAAT-binding factor also plays a role in the regulation of the oxidative stress response in C. albicans (Chakravarti et al, 2017 ). In addition to this, Hap43 represses the GATA family transcription factor Sfu1.…”

Section: Regulation Of Iron Acquisition In Candida Albicansmentioning

confidence: 99%

Iron at the Centre of Candida albicans Interactions

Fourie¹,

Kuloyo²,

Mochochoko³

et al. 2018

Front. Cell. Infect. Microbiol.

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Iron is an absolute requirement for both the host and most pathogens alike and is needed for normal cellular growth. The acquisition of iron by biological systems is regulated to circumvent toxicity of iron overload, as well as the growth deficits imposed by iron deficiency. In addition, hosts, such as humans, need to limit the availability of iron to pathogens. However, opportunistic pathogens such as Candida albicans are able to adapt to extremes of iron availability, such as the iron replete environment of the gastrointestinal tract and iron deficiency during systemic infection. C. albicans has developed a complex and effective regulatory circuit for iron acquisition and storage to circumvent iron limitation within the human host. As C. albicans can form complex interactions with both commensal and pathogenic co-inhabitants, it can be speculated that iron may play an important role in these interactions. In this review, we highlight host iron regulation as well as regulation of iron homeostasis in C. albicans. In addition, the review argues for the need for further research into the role of iron in polymicrobial interactions. Lastly, the role of iron in treatment of C. albicans infection is discussed.

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The Iron-Dependent Regulation of the Candida albicans Oxidative Stress Response by the CCAAT-Binding Factor

Cited by 15 publications

References 69 publications

The Hap Complex in Yeasts: Structure, Assembly Mode, and Gene Regulation

The Hap Complex in Yeasts: Structure, Assembly Mode, and Gene Regulation

The Fungal Histone Acetyl Transferase Gcn5 Controls Virulence of the Human Pathogen Candida albicans through Multiple Pathways

Iron at the Centre of Candida albicans Interactions

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