Potential role of HSP90 in mediating the interactions between estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) signaling pathways

Chang, Ziwei; Lü, Ming; Kim, So‐Sun; Park, Jang-Su

doi:10.1016/j.toxlet.2014.01.032

Cited by 21 publications

(8 citation statements)

References 37 publications

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“…To further understand how IFN suppresses virus, we then used a bioinformatics approach to look for common pathways among the DENV/HCV IEGs and found enrichment for factors related to nuclear receptors, or ligand-activated transcription factors, including peroxisome proliferator associated protein alpha (PPARα) and aryl hydrocarbon receptor (AHR; Figure 1E ). The DENV/HCV IEGs related to nuclear receptors included HELZ2 (Helicase With Zinc Finger 2), a poorly characterized nuclear receptor co-factor (Surapureddi et al, 2002 ; Tomaru et al, 2006 ), and nuclear receptor chaperones (HSP90AA1 and HSP90AB1), as well as other host factors described to interact with nuclear receptors (MAP2K4, SLC27A2; Meyer and Perdew, 1999 ; Bell and Poland, 2000 ; Hirai et al, 2007 ; Lebsack et al, 2010 ; Ahn et al, 2011 ; Garcia-Fuster et al, 2012 ; van Steenbeek et al, 2013 ; Chang et al, 2014 ; Tsuji et al, 2014 ; Figures 1C,D ). Because HELZ2 is an IEG (required for full IFN antiviral effects), an ISG (upregulated by IFN at the mRNA level), and a helicase, therefore possibly serving as a multi-gene regulator, it seemed likely that HELZ2 was truly required for IFN activity, so we then focused on the mechanism through which HELZ2 mediates IFN antiviral effects (Lanford et al, 2006 ; Feld et al, 2007 ; Sarasin-Filipowicz et al, 2008 ; He et al, 2010 ; Fusco et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus

et al. 2017

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Flaviviral infections including dengue virus are an increasing clinical problem worldwide. Dengue infection triggers host production of the type 1 IFN, IFN alpha, one of the strongest and broadest acting antivirals known. However, dengue virus subverts host IFN signaling at early steps of IFN signal transduction. This subversion allows unbridled viral replication which subsequently triggers ongoing production of IFN which, again, is subverted. Identification of downstream IFN antiviral effectors will provide targets which could be activated to restore broad acting antiviral activity, stopping the signal to produce endogenous IFN at toxic levels. To this end, we performed a targeted functional genomic screen for IFN antiviral effector genes (IEGs), identifying 56 IEGs required for antiviral effects of IFN against fully infectious dengue virus. Dengue IEGs were enriched for genes encoding nuclear receptor interacting proteins, including HELZ2, MAP2K4, SLC27A2, HSP90AA1, and HSP90AB1. We focused on HELZ2 (Helicase With Zinc Finger 2), an IFN stimulated gene and IEG which encodes a promiscuous nuclear factor coactivator that exists in two isoforms. The two unique HELZ2 isoforms are both IFN responsive, contain ISRE elements, and gene products increase in the nucleus upon IFN stimulation. Chromatin immunoprecipitation-sequencing revealed that the HELZ2 complex interacts with triglyceride-regulator LMF1. Mass spectrometry revealed that HELZ2 knockdown cells are depleted of triglyceride subsets. We thus sought to determine whether HELZ2 interacts with a nuclear receptor known to regulate immune response and lipid metabolism, AHR, and identified HELZ2:AHR interactions via co-immunoprecipitation, found that AHR is a dengue IEG, and that an AHR ligand, FICZ, exhibits anti-dengue activity. Primary bone marrow derived macrophages from HELZ2 knockout mice, compared to wild type controls, exhibit enhanced dengue infectivity. Overall, these findings reveal that IFN antiviral response is mediated by HELZ2 transcriptional upregulation, enrichment of HELZ2 protein levels in the nucleus, and activation of a transcriptional program that appears to modulate intracellular lipid state. IEGs identified in this study may serve as both (1) potential targets for host directed antiviral design, downstream of the common flaviviral subversion point, as well as (2) possible biomarkers, whose variation, natural, or iatrogenic, could affect host response to viral infections.

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Section: Resultsmentioning

confidence: 99%

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus

et al. 2017

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“…We found that AhR was positively correlated with ER and also to Nrf2 when assessing all samples, with correlations between AhR and ER in the time-integrated samples and AhR and Nrf2 in the flow-proportional samples. Such a correlation could be due to (1) linked biological effects (e.g., interactions between AhR and ER signaling [44,45] and by Nrf2 activation of the AhR pathway [46]), (2) co-presence in the sample of chemicals that are regulating the different biological responses, or (3) that the same chemical affects both pathways. The strong correlation between AhR and Nrf2 in the flow-proportional samples may indicate concomitant release, due to the high flow, of chemicals regulating the two pathways.…”

Section: Discussionmentioning

confidence: 99%

Assessment of pesticides in surface water samples from Swedish agricultural areas by integrated bioanalysis and chemical analysis

et al. 2019

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Background: Pesticide residue contamination of surface water in agricultural areas can have adverse effects on the ecosystem. We have performed an integrated chemical and bioanalytical profiling of surface water samples from Swedish agricultural areas, aiming to assess toxic activity due to presence of pesticides. A total of 157 water samples were collected from six geographical sites with extensive agricultural activity. The samples were chemically analyzed for 129 commonly used pesticides and transformation products. Furthermore, the toxicity was investigated using in vitro bioassays in the water samples following liquid-liquid extraction. Endpoints included oxidative stress response (Nrf2 activity), estrogen receptor (ER) activity, and aryl hydrocarbon receptor (AhR) activity. The bioassays were performed with a final enrichment factor of 5 for the water samples. All bioassays were conducted at non-cytotoxic conditions. Results: A total of 51 pesticides and transformation products were detected in the water samples. Most of the compounds were herbicides, followed by fungicides, insecticides and transformation products. The highest total pesticide concentration in an individual sample was 39 µg/L, and the highest median total concentration at a sample site was 1.1 µg/L. The largest number of pesticides was 31 in a single sample. We found that 3% of the water samples induced oxidative stress response, 23% of the samples activated the estrogen receptor, and 77% of the samples activated the aryl hydrocarbon receptor. Using Spearman correlation coefficients, a statistically significant correlation was observed between AhR and ER activities, and AhR activity was strongly correlated with oxidative stress in samples with a high AhR activity. Statistically significant relationships were observed between bioactivities and individual pesticides, although the relationships are probably not causal, due to the low concentrations of pesticides. Co-occurrence of non-identified chemical pollutants and naturally occurring toxic compounds may be responsible for the induced bioactivities. Conclusions: This study demonstrated that integrated chemical analysis and bioanalysis can be performed in water samples following liquid/liquid extraction with a final enrichment factor of 5. AhR and ER activities were induced in water samples from agricultural areas. The activities were presumably not caused by the occurrence of pesticides, but induced by other anthropogenic and natural chemicals.

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“…This implies that HSP108 protein levels regulated by these gene decrease, indicating that infection by T. gondii influences its expression. HSP108 protein presents a protection profile during infections [ 14 ] that is associated to the hormonal response [ 28 ], inferring that, in cases of infection by T. gondii , the regulation of heat shock protein may also downregulate by negative feedback, making necessary a recruitment of inflammatory cells [ 18 ], possibly interfering in the proper development.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii infection of chicken embryos causes retinal changes and modulates HSP90B1 gene expression: A promising ocular toxoplasmosis model

Násare

Tedesco

Cristovam

et al. 2015

EuJMI

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HSP90B1 is a gene that codifies heat shock protein 108 (HSP108) that belongs to a group of proteins induced under stress situation, and it has close relation with the nervous system, especially in the retina. Toxoplasma gondii causes ocular toxoplasmosis that has been associated with a late manifestation of the congenital toxoplasmosis although experimental models show that morphological alterations are already present during embryological development. Here, we used 18 eyes of Gallus domesticus embryos in 7th and 20th embryonic days to establish a model of congenital ocular toxoplasmosis, experimentally infected in its fifth day correlating with HSP90B1 gene expression. Embryos’ eyes were histologically evaluated, and gene expression was performed by real-time polymerase chain reaction (PCR). Our data showed parasite present in the choroid, unusual migration of retinal pigment epithelium, and chorioretinal scars, and a tendency to a lower expression of the HSP90B1 gene upon experimental infection. This is a promising model to better understand T. gondii etiopathogeny.

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Potential role of HSP90 in mediating the interactions between estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) signaling pathways

Cited by 21 publications

References 37 publications

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus

Assessment of pesticides in surface water samples from Swedish agricultural areas by integrated bioanalysis and chemical analysis

Toxoplasma gondii infection of chicken embryos causes retinal changes and modulates HSP90B1 gene expression: A promising ocular toxoplasmosis model

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