Regulatory involvement of the PerR and SloR metalloregulators in the Streptococcus mutans oxidative stress response

Streptococcus mutans is a commensal of the human oral microbiome that can promote dental caries under conditions of dysbiosis. This study investigates metalloregulators and their involvement in the S. mutans oxidative stress response. Oxidative stress in the human mouth can derive from temporal increases in reactive oxygen species (ROS) after meal consumption and from endogenous bacterial ROS-producers that colonize the dentition. We hypothesize that the S. mutans PerR (SMU.593) and SloR (SMU.186) metalloregulatory proteins contribute to the regulation of oxidative stress genes and their products. Expression assays with S. mutans UA159 wild type cultures exposed to H2O2 reveal that H2O2 upregulates perR, and that PerR represses sloR transcription upon binding directly to Fur and PerR consensus sequences within the sloR operator. In addition, the results of Western blot experiments implicate the Clp proteolytic system in SloR degradation under conditions of H2O2-stress. To reveal a potential role for SloR in the H2O2-resistant phenotype of S. mutans GMS802 (a perR-deficient strain), we generated a sloR/perR double knockout mutant, GMS1386, where we observed upregulation of the tpx and dpr antioxidant genes. These results are consistent with GMS802 H2O2 resistance and with a role for PerR as a transcriptional repressor. Cumulatively, these findings support a reciprocal relationship between PerR and SloR during the S. mutans oxidative stress response and begin to elucidate the fitness strategies that evolved to foster S. mutans persistence in the transient environments of the human oral cavity. IMPORTANCE In 2020, untreated dental caries, especially in the permanent dentition, ranked among the most prevalent infectious diseases worldwide, disproportionately impacting individuals of low socioeconomic status. Untreated caries can lead to systemic health problems and has been associated with extended school and work absences, inappropriate use of emergency departments, and an inability for military forces to deploy. Together with public health policy, research aimed at alleviating S. mutans-induced tooth decay is important because it can improve oral health (and overall health), especially in underserved populations. This research, focused on S. mutans metalloregulatory proteins and their gene targets, is significant because it can promote virulence gene control in an important oral pathogen, and contribute to the development of an anti-caries therapeutic that can reduce tooth decay.

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Regulatory involvement of the PerR and SloR metalloregulators in the Streptococcus mutans oxidative stress response

10.1101/2020.12.15.422995 ◽

2020 ◽

Author(s):

Talia R. Ruxin ◽

Julia A. Schwartzman ◽

Cleo R. Davidowitz ◽

Robet A. Haney ◽

Grace A. Spatafora

Keyword(s):

Oxidative Stress ◽

Dental Caries ◽

Oral Cavity ◽

Streptococcus Mutans ◽

Low Socioeconomic Status ◽

Underserved Populations ◽

Oral Microbiome ◽

Double Knockout ◽

Antioxidant Genes ◽

Metalloregulatory Proteins

ABSTRACTStreptococcus mutans is a commensal of the human oral microbiome that can instigate dental caries under conditions of dysbiosis. This study investigates S. mutans metalloregulators and their involvement in mediating a response to oxidative stress. Oxidative stress in the oral cavity can derive from temporal increases in reactive oxygen species (ROS) after meal consumption, and from endogenous bacterial ROS-producers that colonize the dentition as constituents of dental plaque. We hypothesize that the PerR (SMU.593) and SloR (SMU.186) metalloregulatory proteins in S. mutans contribute to oxidative stress tolerance by regulating the expression of genes responsive to H2O2 challenge. The results of qRT-PCR experiments with S. mutans cultures exposed to 0.5mM H2O2 reveal perR transcription that is responsive to the peroxide stressor, and sloR transcription that is subject to PerR repression. The results of gel shift assays support direct binding of a PerR homolog to the S. mutans sloR promoter at Fur and PerR consensus sequences on the UA159 chromosome. In addition, transcription of the S. mutans tpx and dpr antioxidant genes is upregulated in a perR/sloR double knockout mutant, consistent with heightened resistance of the S. mutans GMS802 perR-deficient strain when challenged with H2O2. Cumulatively, these results reveal a relationship of reciprocity between the PerR and SloR metalloregulators during the S. mutans response to oxidative stress and begin to elucidate the fitness strategies that evolved to foster S. mutans survival and persistence in the transient environments of the human oral cavity.IMPORTANCEIn 2020, untreated dental caries, especially in the permanent dentition, ranked among the most prevalent infectious diseases worldwide. Moreover, caries disproportionately affects children and individuals of low socioeconomic status. Untreated caries can lead to systemic health problems and has been associated with extended school and work absences, inappropriate use of emergency departments, and an inability for military forces to deploy. In combination with public health policy, research aimed at alleviating S. mutans-induced tooth decay is important because it can improve oral health, as well as overall health, especially for underserved populations. This research is focused on the S. mutans SloR and PerR metalloregulatory proteins that can help inform the development of therapeutics aimed at alleviating and potentially preventing dental caries.

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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.

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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.

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

Microorganisms ◽

10.3390/microorganisms7050131 ◽

2019 ◽

Vol 7 (5) ◽

pp. 131 ◽

Cited By ~ 5

Author(s):

Shao-Yu Lee ◽

Hsueh-Fen Chen ◽

Ying-Chieh Yeh ◽

Yao-Peng Xue ◽

Chung-Yu Lan

Keyword(s):

Oxidative Stress ◽

Transcription Factor ◽

Candida Albicans ◽

Stress Response ◽

Oxidative Stress Response ◽

Antifungal Drugs ◽

Wild Type ◽

Antioxidant Genes ◽

Type C ◽

Macrophage Killing

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.

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Histone chaperone FACT complex mediates oxidative stress response to promote liver cancer progression

Gut ◽

10.1136/gutjnl-2019-318668 ◽

2019 ◽

Vol 69 (2) ◽

pp. 329-342 ◽

Cited By ~ 5

Author(s):

Jialing Shen ◽

Mengnuo Chen ◽

Derek Lee ◽

Cheuk-Ting Law ◽

Lai Wei ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Cancer Progression ◽

Transcription Elongation ◽

Complex Form ◽

Histone Chaperone ◽

Oxidative Stress Response ◽

In Vivo Models ◽

Antioxidant Genes ◽

Protein Ubiquitination

ObjectiveFacilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair-related and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms and therapeutic implications in human hepatocellular carcinoma (HCC).DesignWe obtained HCC and its corresponding non-tumorous liver samples from 16 patients and identified FACT complex as the most upregulated histone chaperone by RNA-Seq. We further used CRISPR-based gene activation and knockout systems to demonstrate the functions of FACT complex in HCC growth and metastasis. Functional roles and mechanistic insights of FACT complex in oxidative stress response were investigated by ChIP assay, flow cytometry, gene expression assays and 4sU-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models.ResultsWe showed that FACT complex was remarkably upregulated in HCC and contributed to HCC progression. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilised NRF2 and FACT complex form a positive feedback loop; NRF2 transcriptionally activates the FACT complex, while FACT complex promotes the transcription elongation of NRF2 and its downstream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Therapeutically, Curaxin effectively suppressed HCC growth and sensitised HCC cell to sorafenib.ConclusionIn conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.

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Oxidative stress response plays a role in antibiotic tolerance of Streptococcus mutans biofilms

Microbiology ◽

10.1099/mic.0.000773 ◽

2019 ◽

Vol 165 (3) ◽

pp. 334-342 ◽

Cited By ~ 6

Author(s):

Martin Nilsson ◽

Tim Holm Jakobsen ◽

Michael Givskov ◽

Svante Twetman ◽

Tim Tolker-Nielsen

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Streptococcus Mutans ◽

Oxidative Stress Response ◽

Antibiotic Tolerance

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Targeting Nrf2-Mediated Oxidative Stress Response Signaling Pathways as New Therapeutic Strategy for Pituitary Adenomas

Frontiers in Pharmacology ◽

10.3389/fphar.2021.565748 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xianquan Zhan ◽

Jiajia Li ◽

Tian Zhou

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Signaling Pathways ◽

Anticancer Agents ◽

Pituitary Adenomas ◽

Therapeutic Strategy ◽

Mapk Signaling ◽

Oxidative Stress Response ◽

Phase Iii ◽

Antioxidant Genes

Oxidative stress and oxidative damage are the common pathophysiological characteristics in pituitary adenomas (PAs), which have been confirmed with many omics studies in PA tissues and cell/animal experimental studies. Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), the core of oxidative stress response, is an oxidative stress sensor. Nrf2 is synthesized and regulated by multiple factors, including Keap1, ERK1/2, ERK5, JNK1/2, p38 MAPK, PKC, PI3K/AKT, and ER stress, in the cytoplasm. Under the oxidative stress status, Nrf2 quickly translocates from cytoplasm into the nucleus and binds to antioxidant response element /electrophile responsive element to initiate the expressions of antioxidant genes, phases I and II metabolizing enzymes, phase III detoxifying genes, chaperone/stress response genes, and ubiquitination/proteasomal degradation proteins. Many Nrf2 or Keap1 inhibitors have been reported as potential anticancer agents for different cancers. However, Nrf2 inhibitors have not been studied as potential anticancer agents for PAs. We recommend the emphasis on in-depth studies of Nrf2 signaling and potential therapeutic agents targeting Nrf2 signaling pathways as new therapeutic strategies for PAs. Also, the use of Nrf2 inhibitors targeting Nrf2 signaling in combination with ERK inhibitors plus p38 activators or JNK activators targeting MAPK signaling pathways, or drugs targeting mitochondrial dysfunction pathway might produce better anti-tumor effects on PAs. This perspective article reviews the advances in oxidative stress and Nrf2-mediated oxidative stress response signaling pathways in pituitary tumorigenesis, and the potential of targeting Nrf2 signaling pathways as a new therapeutic strategy for PAs.

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