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Functional analysis of Rousettus aegyptiacus "signal transducer and activator of transcription 1" (STAT1).

ABSTRACT: Bats are now known as the source of several diseases in humans, but few studies regarding immune responses and factors associated with bats have so far been reported. In this study, we focused on STAT1, one of the critical components in interferon (IFN)-signaling and antiviral activity, which is often targeted by viral proteins to reduce antiviral activity and increase viral replication. We found that Rousettus aegyptiacus STAT1 (bat STAT1) is phosphorylatable and translocates to the nucleus when stimulated with human IFN-alpha (hIFN-alpha). Furthermore, phosphorylation of bat STAT1 and inhibition of nuclear translocation was observed in IFN-stimulated cells infected with the HEP-Flury strain of rabies virus, in the same manner as in other mammals. Additionally, quantitative real-time RT-PCR revealed that bat STAT1 mRNA was highly expressed in the liver, while low in muscle and spleen.

SUBMITTER: Fujii H

PROVIDER: S-EPMC7103214 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis.

Project description:BackgroundImpaired signaling in the IFN-?/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis.ObjectiveWe sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.MethodsPBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-?/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated.ResultsWe identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-?-induced gene expression, but we found impaired responses to IFN-? restimulation.ConclusionGain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-?-mediated inflammation.

| S-EPMC3746066 | biostudies-literature

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes.

Project description:Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling-it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.

| S-EPMC7927067 | biostudies-literature

Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations.

Project description:BACKGROUND:Natural killer (NK) cells are critical innate effector cells whose development is dependent on the Janus kinase-signal transducer and activator of transcription (STAT) pathway. NK cell deficiency can result in severe or refractory viral infections. Patients with STAT1 gain-of-function (GOF) mutations have increased viral susceptibility. OBJECTIVE:We sought to investigate NK cell function in patients with STAT1 GOF mutations. METHODS:NK cell phenotype and function were determined in 16 patients with STAT1 GOF mutations. NK cell lines expressing patients' mutations were generated with clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)-mediated gene editing. NK cells from patients with STAT1 GOF mutations were treated in vitro with ruxolitinib. RESULTS:Peripheral blood NK cells from patients with STAT1 GOF mutations had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57, and impaired cytolytic function. STAT1 phosphorylation was increased, but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT1 signaling with the small-molecule Janus kinase 1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function. CONCLUSIONS:Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

| S-EPMC5924437 | biostudies-literature

Genes induced by PDGF-BB in cells lacking Signal Transducer and Activator of Transcription-1 (Stat1)

Project description:Comparison of gene expression between Stat1+/- and Stat1-/- dermal fibroblasts or vascular smooth muscle cells after treatment with PDGF-BB for one hour.

2020-06-13 | GSE152342 | GEO

A novel mechanism of skin tumor promotion involving interferon-gamma (IFN?)/signal transducer and activator of transcription-1 (Stat1) signaling.

Project description:The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O-tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFN?) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFN? signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFN? signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1.

| S-EPMC4139479 | biostudies-literature

Signal transducer and activator of transcription 4 in liver diseases.

Project description:STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. STAT4 activation is detected virtually in the liver of several mouse models of liver injury, as well as the human liver of chronic liver diseases. STAT4 gene polymorphism has been shown to be associated with the antiviral response in chronic hepatitis C and drug-induced liver injury (DILI), primary biliary cirrhosis (PBC), HCV-associated liver fibrosis and in hepatocellular carcinoma (HCC). However, the roles of STAT4 in the pathogeneses of liver diseases are still not understood entirely. This review summarizes the recent advances on the functional roles of STAT4 and its related cytokines in liver diseases, especially in regulating hepatic anti-viral responses, inflammation, proliferation, apoptosis and tumorigenesis. Targeting STAT4 signaling pathway might be a promising strategy in developing therapeutic approaches for treating hepatitis in order to prevent further injury like cirrhosis and liver cancer.

| S-EPMC4366643 | biostudies-literature

Rousettus aegyptiacus aegyptiacus

Project description:Rousettus aegyptiacus aegyptiacus Proteomic

| PRJNA514339 | ENA

Rousettus aegyptiacus aegyptiacus

Project description:Rousettus aegyptiacus aegyptiacus Genome sequencing and assembly

| PRJNA297210 | ENA

Signal transducer and activator of transcription 6 polymorphism and asthma risk: a meta-analysis.

Project description:BackgroundThe polymorphism in the signal transducer and activators of transduction 6 (STAT6) gene has been implicated in susceptibility to asthma and aetiology of asthma, but a number of studies have reported inconclusive and ambiguous results of the association between polymorphism in STAT6 gene and asthma risk in different populations. The aim of this study is to further investigate the association between the STAT6 gene polymorphism and asthma susceptibility.MethodsPubmed, EMBASE, China National Knowledge Infrastructure (CNKI) Weipu Database and Wanfang Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.ResultsIncluded in this meta analysis were 14 studies involving 2875 cases and 3227 controls for STAT6 2964G/A polymorphism and six studies involving 1431 cases and 2027 controls for 2892C/T polymorphism. Overall, there was no significant association between 2964G/A polymorphism of STAT6 and asthma susceptibility for GA+AA vs. GG (OR = 0.96, 95% CI 0.85-1.07, P = 0.39). Except TT vs. CT+CC and TT vs. CC, no significant association was observed between 2892C/T polymorphism and asthma risk under other different contrast models. However, the result was instable.ConclusionsThis meta-analysis suggests that the 2964G/A polymorphism of STAT6 gene is not a risk factor of asthma. For 2892C/T, it contributes to the aetiology of or susceptibility to asthma. More studies are needed to validate this result.

| S-EPMC3762616 | biostudies-literature

Israeli Rousettus aegyptiacus Pox Virus (IsrRAPXV) Infection in Juvenile Egyptian Fruit Bat (Rousettus aegyptiacus): Clinical Findings and Molecular Detection.

Project description:During 2019, five carcasses of juvenile Egyptian fruit bats (Rousettus aegyptiacus) were submitted to the Kimron Veterinary Institute. These bats exhibited typical poxvirus like lesion plaques of different sizes on the skin, abdomen and the ventral side of the wings. Clinical and histopathological findings suggested a poxvirus infection. Infectious virus was isolated from skin swabs, skin tissue and tongue of the dead bats and was further confirmed to be a Poxvirus by molecular diagnosis using PCR with pan-chordopoxviruses primers. All the dead bats were found positive for two Poxvirus genes encoding a metalloproteinase and DNA dependent DNA polymerase. In this study, a novel real time quantitative PCR (qPCR) assay was established to further confirmed the presence of specific poxvirus viral DNA in all pathologically tested tissues. Moreover, according to sequence analysis, the virus was found to be highly similar to the recently discovered Israeli Rousettus aegyptiacus Pox Virus (IsrRAPXV).

| S-EPMC8001970 | biostudies-literature

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