The Transcription Factor Sfp1 Regulates the Oxidative Stress Response in Candida albicans

Candida albicans is a commensal that inhabits the skin and mucous membranes of humans. Because of the increasing immunocompromised population and the limited classes of antifungal drugs available, C. albicans has emerged as an important opportunistic pathogen with high mortality rates. During infection and therapy, C. albicans frequently encounters immune cells and antifungal drugs, many of which exert their antimicrobial activity by inducing the production of reactive oxygen species (ROS). Therefore, antioxidative capacity is important for the survival and pathogenesis of C. albicans. In this study, we characterized the roles of the zinc finger transcription factor Sfp1 in the oxidative stress response against C. albicans. A sfp1-deleted mutant was more resistant to oxidants and macrophage killing than wild-type C. albicans and processed an active oxidative stress response with the phosphorylation of the mitogen-activated protein kinase (MAPK) Hog1 and high CAP1 expression. Moreover, the sfp1-deleted mutant exhibited high expression levels of antioxidant genes in response to oxidative stress, resulting in a higher total antioxidant capacity, glutathione content, and glutathione peroxidase and superoxide dismutase enzyme activity than the wild-type C. albicans. Finally, the sfp1-deleted mutant was resistant to macrophage killing and ROS-generating antifungal drugs. Together, our findings provide a new understanding of the complex regulatory machinery in the C. albicans oxidative stress response.

Download Full-text

PICH, an ATP-dependent chromatin remodeling protein, transcriptionally co-regulates oxidative stress response.

10.1101/2021.07.21.453306 ◽

2021 ◽

Author(s):

Anindita Dutta ◽

Apurba Das ◽

Deep Bisht ◽

Vijendra Arya ◽

Rohini Muthuswami

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Transcriptional Regulation ◽

Stress Response ◽

Chromatin Remodeling ◽

Dna Sequences ◽

Target Genes ◽

Antioxidant Response ◽

Oxidative Stress Response ◽

Antioxidant Genes

Cells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation often implemented by chromatin remodeling proteins. The study presented in this paper shows that the expression of PICH, an ATP-dependent chromatin remodeler, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response, both in the absence and presence of oxidative stress. In turn, Nrf2 regulates the expression of PICH in the presence of oxidative stress. Both PICH and Nrf2 together regulate the expression of antioxidant genes and this transcriptional regulation is dependent on the ATPase activity of PICH. In addition, H3K27ac modification also plays a role in activating transcription in the presence of oxidative stress. Co-immunoprecipitation experiments show that PICH and Nrf2 interact with H3K27ac in the presence of oxidative stress. Mechanistically, PICH recognizes ARE sequences present on its target genes and introduces a conformational change to the DNA sequences leading us to hypothesize that PICH regulates transcription by remodeling DNA. PICH ablation leads to reduced expression of Nrf2 and impaired antioxidant response leading to increased ROS content, thus, showing PICH is essential for the cell to respond to oxidative stress.

Download Full-text

The OxyR homologue in Tannerella forsythia regulates expression of oxidative stress responses and biofilm formation

Microbiology ◽

10.1099/mic.0.027920-0 ◽

2009 ◽

Vol 155 (6) ◽

pp. 1912-1922 ◽

Cited By ~ 36

Author(s):

Kiyonobu Honma ◽

Elina Mishima ◽

Satoru Inagaki ◽

Ashu Sharma

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Biofilm Formation ◽

Type Strain ◽

Wild Type Strain ◽

Oxidative Stress Response ◽

Wild Type ◽

Tannerella Forsythia ◽

Antioxidant Genes

Tannerella forsythia is an anaerobic periodontal pathogen that encounters constant oxidative stress in the human oral cavity due to exposure to air and reactive oxidative species from coexisting dental plaque bacteria as well as leukocytes. In this study, we sought to characterize a T. forsythia ORF with close similarity to bacterial oxidative stress response sensor protein OxyR. To analyse the role of this OxyR homologue, a gene deletion mutant was constructed and characterized. Aerotolerance, survival after hydrogen peroxide challenge and transcription levels of known bacterial antioxidant genes were then determined. Since an association between oxidative stress and biofilm formation has been observed in bacterial systems, we also investigated the role of the OxyR protein in biofilm development by T. forsythia. Our results showed that aerotolerance, sensitivity to peroxide challenge and the expression of oxidative stress response genes were significantly reduced in the mutant as compared with the wild-type strain. Moreover, the results of biofilm analyses showed that, as compared with the wild-type strain, the oxyR mutant showed significantly less autoaggregation and a reduced ability to form mixed biofilms with Fusobacterium nucleatum. In conclusion, a gene annotated in the T. forsythia genome as an oxyR homologue was characterized. Our studies showed that the oxyR homologue in T. forsythia constitutively activates antioxidant genes involved in resistance to peroxides as well as oxygen stress (aerotolerance). In addition, the oxyR deletion attenuates biofilm formation in T. forsythia.

Download Full-text

Systematic Identification and Characterization of Five Transcription Factors Mediating the Oxidative Stress Response in Candida Albicans

10.21203/rs.3.rs-121956/v1 ◽

2020 ◽

Author(s):

YingChao Cui ◽

DaoSheng Wang ◽

Clarissa J. Nobile ◽

Danfeng Dong ◽

Qi Ni ◽

...

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Candida Albicans ◽

Transcription Factors ◽

Stress Response ◽

Oxidative Stress Response ◽

Functional Enrichment ◽

Fungal Virulence ◽

Potent Inducer ◽

Mutant Strains

Abstract BackgroundCandida albicans is an opportunistic human fungal pathogen that can cause both superficial and systemic infections, especially in immunocompromised individuals. In response to C. albicans infections, innate immune cells of the host produce and accumulate reactive oxygen species (ROS) that can lead to irreversible damage and apoptosis of fungal cells. Prior studies have identified several transcription factors involved in the oxidative stress response of C. albicans. However, a systematic study to identify transcription factors mediating the oxidative response had not been previously conducted. ResultsIn this study, we screened a comprehensive transcription factor mutant library consisting of 211 transcription factor deletion mutant strains in the presence and absence of H2O2, a potent inducer of ROS, and identified five transcription factors (Skn7, Dpb4, Cap1, Dal81 and Stp2) involved in the response to H2O2. Genome-wide transcriptional profiling revealed that H2O2 induced a discreet set of genes differentially regulated in common among the five transcription factor mutant strains identified. Functional enrichment analysis identified KEGG pathways pertaining to glycolysis/gluconeogenesis, amino sugar and nucleotide sugar metabolism, and ribosome synthesis as the most enriched pathways. Furthermore, among the most common differentially expressed genes, hexose catabolism and iron transport were the most enriched GO terms.ConclusionsOur study is the first to systematically identify and characterize transcription factors involved in the response to H2O2. Based on the transcription factors identified, we found that exposure to H2O2 modulates several downstream gene classes involved in fungal virulence. Overall, this study sheds new light on the metabolism, physiological functions and cellular processes involved in the H2O2-induced oxidative stress response in C. albicans.

Download Full-text

Extending the proteomic characterization of Candida albicans exposed to stress and apoptotic inducers through data-independent acquisition mass espectrometry

Access Microbiology ◽

10.1099/acmi.cc2021.po0087 ◽

2021 ◽

Vol 3 (12) ◽

Author(s):

Ahinara Amador-García ◽

Johan Malmström ◽

Lucia Monteoliva ◽

Concha Gil

Keyword(s):

Oxidative Stress ◽

Protein Folding ◽

Candida Albicans ◽

Stress Response ◽

Oxidative Stress Response ◽

Antifungal Drugs ◽

Proteasome Activity ◽

Main Role ◽

Data Independent Acquisition ◽

Almost All

Candida albicans is a commensal fungus that causes systemic infections in immunosuppressed patients. In order to deal with the changing environment during commensalism or infection, C. albicans must reprogram its proteome. Characterizing the stress-induced changes in the proteome that C. albicans uses to survive should be very useful in the development of new antifungal drugs. We studied the C. albicans global proteome after exposure to hydrogen peroxide (H2O2) and acetic acid (AA), using a DIA-MS strategy. More than 2000 C. albicans proteins were quantified using an ion library previously constructed using DDA-MS. C. albicans responded to treatment with H2O2 with an increase in the abundance of many proteins involved in the oxidative stress response, protein folding and proteasome-dependent catabolism, which led to an increased proteasome activity. The data revealed a previously unknown key role for Prn1, a protein similar to pirins, in the oxidative stress response. Treatment with AA resulted in a general decrease in the abundance of proteins involved in amino acid biosynthesis, protein folding, and rRNA processing. Almost all proteasome proteins declined, as did proteasome activity. Apoptosis was observed after treatment with H2O2, but not AA. A targeted proteomic study of 32 proteins related to apoptosis in yeast supported the results found by DIA-MS and allowed the creation of an efficient method to quantify relevant proteins after treatment with stressors (H2O2, AA, and amphotericin B). This approach also uncovered a main role for Oye32, an oxidoreductase, suggesting this protein as a possible apoptotic marker common to many stressors.

Download Full-text