Staab, Julia F.

[["dc.contributor.author","Nast, Roswitha"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Meyer, Thomas"],["dc.contributor.editor","Behzadi, Payam"],["dc.date.accessioned","2019-08-07T07:32:36Z"],["dc.date.available","2019-08-07T07:32:36Z"],["dc.date.issued","2019"],["dc.description.abstract","Signal transducers and activators of transcription (STATs) are a family of cytokine-regulated transcription factors, which serve the dual role of external signal transduction and transcriptional activation. The founding member of this family, STAT1, is involved in a plethora of cellular processes, including interferon-dependent upregulation of various effector mechanisms in immune and non-immune cells to control bacterial, fungal and parasitic infections. In this chapter, we discuss the principles of STAT1-driven gene expression and focus on the clinical phenotypes of various human STAT1 mutations. In particular, we highlight the significance of sequence-specific DNA binding and intact nucleocytoplasmic shuttling for full transcriptional activation of interferon-driven target genes."],["dc.identifier.doi","10.5772/intechopen.82699"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62332"],["dc.language.iso","en"],["dc.notes.status","zu prüfen"],["dc.relation.isbn","978-1-78985-683-5"],["dc.relation.isbn","978-1-78985-684-2"],["dc.relation.ispartof","Gene Regulation"],["dc.title","Gene Activation by the Cytokine-Driven Transcription Factor STAT1"],["dc.type","book_chapter"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","A143"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Psychosomatic Medicine"],["dc.bibliographiccitation.lastpage","A144"],["dc.bibliographiccitation.volume","78"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T10:15:43Z"],["dc.date.available","2018-11-07T10:15:43Z"],["dc.date.issued","2016"],["dc.identifier.isi","000373949800470"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40870"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Lippincott Williams & Wilkins"],["dc.publisher.place","Philadelphia"],["dc.relation.conference","74th Annual Meeting of the American-Psychosomatic-Society"],["dc.relation.eventlocation","Denver, CO"],["dc.relation.issn","1534-7796"],["dc.relation.issn","0033-3174"],["dc.title","SITE-DIRECTED MUTAGENESIS OF STAT1 TRANSCRIPTION FACTOR IN THE STUDY OF INTERFERON-INDUCED DEPRESSION"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","11193"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","International Journal of Environmental Research and Public Health"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Veiz, Elisabeth"],["dc.contributor.author","Kieslich, Susann-Kristin"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Czesnik, Dirk"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2021-12-01T09:22:50Z"],["dc.date.available","2021-12-01T09:22:50Z"],["dc.date.issued","2021"],["dc.description.abstract","This paper presents data from a transcutaneous vagus nerve stimulation experiment that point towards a blunted cardiac baroreceptor sensitivity (cBRS) in young males compared to females during electrical stimulation of the forearm and a rhythmic breathing task. Continuous electrocardiography, impedance cardiography and continuous blood-pressure recordings were assessed in a sex-matched cohort of twenty young healthy subjects. Electrical stimulation of the median nerve was conducted by using a threshold-tracking method combined with two rhythmic breathing tasks (0.1 and 0.2 Hz) before, during and after active or sham transcutaneous vagus nerve stimulation. Autonomic and hemodynamic parameters were calculated, and differences were analyzed by using linear mixed models and post hoc F-tests. None of the autonomic and hemodynamic parameters differed between the sham and active conditions. However, compared to females, male participants had an overall lower total cBRS independent of stimulation condition during nerve stimulation (females: 14.96 ± 5.67 ms/mmHg, males: 11.89 ± 3.24 ms/mmHg, p = 0.031) and rhythmic breathing at 0.2 Hz (females: 21.49 ± 8.47 ms/mmHg, males: 15.12 ± 5.70 ms/mmHg, p = 0.004). Whereas vagus nerve stimulation at the left inner tragus did not affect the efferent vagal control of the heart, we found similar patterns of baroreceptor sensitivity activation over the stimulation period in both sexes, which, however, significantly differed in their magnitude, with females showing an overall higher cBRS."],["dc.description.abstract","This paper presents data from a transcutaneous vagus nerve stimulation experiment that point towards a blunted cardiac baroreceptor sensitivity (cBRS) in young males compared to females during electrical stimulation of the forearm and a rhythmic breathing task. Continuous electrocardiography, impedance cardiography and continuous blood-pressure recordings were assessed in a sex-matched cohort of twenty young healthy subjects. Electrical stimulation of the median nerve was conducted by using a threshold-tracking method combined with two rhythmic breathing tasks (0.1 and 0.2 Hz) before, during and after active or sham transcutaneous vagus nerve stimulation. Autonomic and hemodynamic parameters were calculated, and differences were analyzed by using linear mixed models and post hoc F-tests. None of the autonomic and hemodynamic parameters differed between the sham and active conditions. However, compared to females, male participants had an overall lower total cBRS independent of stimulation condition during nerve stimulation (females: 14.96 ± 5.67 ms/mmHg, males: 11.89 ± 3.24 ms/mmHg, p = 0.031) and rhythmic breathing at 0.2 Hz (females: 21.49 ± 8.47 ms/mmHg, males: 15.12 ± 5.70 ms/mmHg, p = 0.004). Whereas vagus nerve stimulation at the left inner tragus did not affect the efferent vagal control of the heart, we found similar patterns of baroreceptor sensitivity activation over the stimulation period in both sexes, which, however, significantly differed in their magnitude, with females showing an overall higher cBRS."],["dc.identifier.doi","10.3390/ijerph182111193"],["dc.identifier.pii","ijerph182111193"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/94492"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-478"],["dc.publisher","MDPI"],["dc.relation.eissn","1660-4601"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Men Show Reduced Cardiac Baroreceptor Sensitivity during Modestly Painful Electrical Stimulation of the Forearm: Exploratory Results from a Sham-Controlled Crossover Vagus Nerve Stimulation Study"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","108"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","ZEITSCHRIFT FUR PSYCHOSOMATISCHE MEDIZIN UND PSYCHOTHERAPIE"],["dc.bibliographiccitation.lastpage","109"],["dc.bibliographiccitation.volume","63"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T10:28:51Z"],["dc.date.available","2018-11-07T10:28:51Z"],["dc.date.issued","2017"],["dc.identifier.isi","000396100900075"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/43515"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Vandenhoeck & Ruprecht"],["dc.publisher.place","Gottingen"],["dc.relation.issn","2196-8349"],["dc.relation.issn","1438-3608"],["dc.title","Mechanisms of depressive Stress Responses in response to Interferon Administration: Mutagenesis of the Transcription Factor STAT1 in the Study of Interferon-induced Depression"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","234"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Gene"],["dc.bibliographiccitation.lastpage","238"],["dc.bibliographiccitation.volume","586"],["dc.contributor.author","Kobbe, Robin"],["dc.contributor.author","Kolster, Manuela"],["dc.contributor.author","Fuchs, Sebastian"],["dc.contributor.author","Schulze-Sturm, Ulf"],["dc.contributor.author","Jenderny, Jutta"],["dc.contributor.author","Kochhan, Lothar"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Tolosa, Eva"],["dc.contributor.author","Grimbacher, Bodo"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T10:11:30Z"],["dc.date.available","2018-11-07T10:11:30Z"],["dc.date.issued","2016"],["dc.description.abstract","Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-alpha (IFN alpha) and/or IFN gamma resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFN alpha/gamma-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms. (C) 2016 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.gene.2016.04.006"],["dc.identifier.isi","000376696100006"],["dc.identifier.pmid","27063510"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40059"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Bv"],["dc.relation.issn","1879-0038"],["dc.relation.issn","0378-1119"],["dc.title","Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e69903"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:22:18Z"],["dc.date.available","2018-11-07T09:22:18Z"],["dc.date.issued","2013"],["dc.description.abstract","A transition from a parallel to an antiparallel dimer configuration of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for interferon (IFN)-mediated signal transduction. However, the precise molecular mechanisms linking conformational changes to target gene activation by STAT1 are still largely unknown. In the present study, we have characterized, in more detail than before, two disease-associated point mutants with amino acid substitutions at both sites of the dimer interface (F172W and T385A). First, we confirmed that IFN gamma-stimulation of transfected cells led to enhanced tyrosine phosphorylation of mutant STAT1 as compared to the wild-type protein, which consequently resulted in its prolonged nuclear accumulation. Using an in vitro dephosphorylation assay, we demonstrated that, in contrast to wild-type STAT1 and similar to the F172W mutant, also T385A resisted enzymatic inactivation by the nuclear phosphatase Tc45. Transcriptional activation of IFN gamma-driven endogenous target genes differed between wild-type and mutant STAT1. While expression of genes containing a single classical gamma-activated site (GAS), such as irf1, gpb1, and mig1, was virtually unaffected by the presence of either of two amino acid exchanges, induction of the cxcl10 and mcp1 gene was significantly enhanced. The latter two genes both contain an additional TTC/GAA binding motif separated by 10 bp from the palindromic GAS sequence. The transcriptional superiority of the mutants on these genes was reflected by their increased binding affinity to DNA fragments containing the identified \"one-and-a-half-GAS\" motif. In summary, our data demonstrate that two clinically relevant interface mutants of STAT1 exhibit gene-specific effects and point to the rather complex role of the assumed conformational shift between two different dimer configurations for efficient transcriptional regulation."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.1371/journal.pone.0069903"],["dc.identifier.isi","000322838900107"],["dc.identifier.pmid","23922848"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/9174"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29312"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY-NC 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/3.0"],["dc.title","Clinically Relevant Dimer Interface Mutants of STAT1 Transcription Factor Exhibit Differential Gene Expression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","22"],["dc.bibliographiccitation.journal","BMC Cell Biology"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Koch, Verena"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Ruppert, Volker"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:07:06Z"],["dc.date.available","2018-11-07T09:07:06Z"],["dc.date.issued","2012"],["dc.description.abstract","Background: In interferon-gamma-stimulated cells, the dimeric transcription factor STAT1 (signal transducer and activator of transcription 1) recognizes semi-palindromic motifs in the promoter regions of cytokine-driven target genes termed GAS (gamma-activated sites). However, the molecular steps that facilitate GAS binding and the subsequent liberation of STAT1 homodimers from these promoter elements are not well understood. Results: Using a mutational approach, we identified two critical glutamyl residues within the DNA-binding domain adjacent to the phosphodiester backbone of DNA which efficiently release phospho-STAT1 from DNA. The release of STAT1 dimers from DNA enhances transcriptional activity on both interferon-driven reporter and endogenous target genes. A substitution of either of the two glutamic acid residues broadens the repertoire of putative binding sites on DNA and enhances binding affinity to GAS sites. However, despite elevated levels of tyrosine phosphorylation and a prolonged nuclear accumulation period, the STAT1 DNA-binding mutants show a significantly reduced transcriptional activity upon stimulation of cells with interferon-gamma. This reduced transcriptional response may be explained by the deposition of oligomerized STAT1 molecules outside GAS sites. Conclusions: Thus, two negatively charged amino acid residues in the DNA-binding domain are engaged in the liberation of STAT1 from DNA, resulting in a high dissociation rate from non-GAS sites as a key feature of STAT1 signal transduction, which positively regulates cytokine-dependent gene expression probably by preventing retention at transcriptionally inert sites."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2012"],["dc.identifier.doi","10.1186/1471-2121-13-22"],["dc.identifier.isi","000311905000001"],["dc.identifier.pmid","22920460"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/8363"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25711"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1471-2121"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.title","Two glutamic acid residues in the DNA-binding domain are engaged in the release of STAT1 dimers from DNA"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","596"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Molecular Immunology"],["dc.bibliographiccitation.lastpage","606"],["dc.bibliographiccitation.volume","67"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Riebeling, Theresa"],["dc.contributor.author","Koch, Verena"],["dc.contributor.author","Herrmann-Lingen, Christoph"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2018-11-07T09:51:03Z"],["dc.date.available","2018-11-07T09:51:03Z"],["dc.date.issued","2015"],["dc.description.abstract","Defective cooperative DNA binding of STAT1 (signal transducer and activator of transcription 1) transcription factor has impact on interferon-gamma(IFN gamma)-regulated transcriptional responses. In this study, we generated N-terminal gain-of-function mutants of this protein which exhibited hyperactive cooperativity and assessed their functional consequences on gene expression. Our data show that four negatively charged, surface-exposed amino acid residues in the N-terminal domain dimer are engaged in the disassembly of tyrosine-phosphorylated tetrameric complexes on DNA and prevent the occurrence of higher-order STAT1 oligomers on low-affinity DNA binding sites. Owing to their improved tetramer stability, the N-terminal mutants showed relaxed sequence requirements for the binding to DNA as compared to the wild-type protein. Similarly to a STAT1 mutant with impaired tetramerization, the N-terminal gain-of-function mutants showed elevated tyrosine-phosphorylation levels and prolonged nuclear accumulation upon stimulation of cells with IFN gamma. However, in contrast to the global impairment of IFN gamma signalling in tetramerization-deficient mutants, the transcriptional consequences of the N-terminal gain-of-function mutants are rather distinct and affect gene expression locally in a promoter-specific manner. Thus, we conclude that the STAT1 N-domain acts as a double-edged sword: while one interface is crucial for the formation of tetrameric complexes on IFN gamma-regulated promoters, the opposite interface harbours an inhibitory mechanism that limits the accumulation of higher-order oligomers simply by disrupting cooperative DNA binding. (C) 2015 Published by Elsevier Ltd."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG) [1816]; DFG"],["dc.identifier.doi","10.1016/j.molimm.2015.07.015"],["dc.identifier.isi","000361922400045"],["dc.identifier.pmid","26275341"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35836"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","0161-5890"],["dc.title","The two interfaces of the STAT1 N-terminus exhibit opposite functions in IFN gamma-regulated gene expression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","23"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","BMC Molecular and Cell Biology"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Behrendsen, Lena Sophie"],["dc.contributor.author","Menon, Priyanka Rajeev"],["dc.contributor.author","Khan, Muhammad Jawad"],["dc.contributor.author","Gregus, Anke"],["dc.contributor.author","Wirths, Oliver"],["dc.contributor.author","Meyer, Thomas"],["dc.contributor.author","Staab, Julia"],["dc.date.accessioned","2022-07-01T07:35:21Z"],["dc.date.available","2022-07-01T07:35:21Z"],["dc.date.issued","2022"],["dc.date.updated","2022-07-25T11:18:51Z"],["dc.description.abstract","Background Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that promotes cell proliferation and immunomodulation in untransformed cells and maintains stemness of transformed cells, facilitating invasion and metastasis. Numerous point mutations in the STAT3 protein have been identified that drive malignancy in various tumor entities. The missense mutation D427H localized in the STAT3 DNA-binding domain has been previously reported in patients with NK/T cell lymphomas. To assess the biological activity of this missense mutation, we compared the STAT3-D427H mutant to wild-type (WT) protein as well as the known hyper-active mutant F174A. Results Although previously reported as an activating mutation, the STAT3-D427H mutant neither showed elevated cytokine-induced tyrosine phosphorylation nor altered nuclear accumulation, as compared to the WT protein. However, the D427H mutant displayed enhanced binding to STAT-specific DNA-binding sites but a reduced sequence specificity and dissociation rate from DNA, which was demonstrated by electrophoretic mobility shift assays. This observation is consistent with the phenotype of the homologous E421K mutation in the STAT1 protein, which also displayed enhanced binding to DNA but lacked a corresponding increase in transcriptional activity. Conclusions Based on our data, it is unlikely that the D427H missense mutation in the STAT3 protein possesses an oncogenic potential beyond the WT molecule."],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Georg-August-Universität Göttingen 501100003385"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.citation","BMC Molecular and Cell Biology. 2022 Jun 25;23(1):23"],["dc.identifier.doi","10.1186/s12860-022-00422-9"],["dc.identifier.pii","422"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112146"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-581"],["dc.relation.eissn","2661-8850"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Lymphoma-associated missense mutation"],["dc.subject","Signal transducer and activator of transcription 3 (STAT3)"],["dc.subject","Interleukin-6 signaling"],["dc.subject","DNA binding"],["dc.subject","Gene expression"],["dc.title","Evaluation of the putative lymphoma-associated point mutation D427H in the STAT3 transcription factor"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e12887"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Cellular Microbiology"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Nast, Roswitha"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Meyer, Thomas"],["dc.contributor.author","Lüder, Carsten G. K."],["dc.date.accessioned","2019-08-07T07:16:19Z"],["dc.date.available","2019-08-07T07:16:19Z"],["dc.date.issued","2018"],["dc.description.abstract","Toxoplasma gondii is an obligate intracellular parasite that infects up to 30% of humans worldwide. It can lead to severe diseases particularly in individuals with immature or defective immune responses. Control of T. gondii relies on the IFN-γ-induced signal transducer and activator of transcription-1 (STAT1) pathway. T. gondii, however, largely inactivates STAT1-mediated gene transcription by T. gondii inhibitor of STAT1-dependent transcription (TgIST), a parasite effector protein binding to STAT1. Here, we have analysed requirements of STAT1 to bind TgIST and characterised downstream effects on STAT1 signalling. TgIST bound to STAT1 dimers but more efficiently assembled with STAT1 tetramers, which are essential for effective IFN-γ responsiveness. Such binding was abrogated in N-terminal, but not C-terminal deletion mutants of STAT1. Furthermore, TgIST did not bind to the STAT1F77A substitution mutant that cannot form STAT1 tetramers, resulting in a complete unresponsiveness of parasite-infected STAT1F77A -expressing cells to IFN-γ. Remarkably, binding of TgIST considerably increased the affinity of the aberrant STAT1 tetramers for DNA consensus sequence binding motifs and even enabled binding to nonconsensus sequences. Consistent with the increased DNA binding, STAT1 from parasite-infected cells remained phosphorylated at Tyr701 and Ser727 and was retained within the nucleus in a DNA-bound state. The sustained and promiscuous binding activity particularly of STAT1 tetramers to unspecific DNA sites lacking a consensus STAT1-binding motif is an as yet unrecognised mechanism contributing to the defective IFN-γ-mediated signalling in T. gondii-infected cells."],["dc.identifier.doi","10.1111/cmi.12887"],["dc.identifier.pmid","29968354"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62329"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1462-5822"],["dc.relation.issn","1462-5814"],["dc.title","Toxoplasma gondii stabilises tetrameric complexes of tyrosine-phosphorylated signal transducer and activator of transcription-1 and leads to its sustained and promiscuous DNA binding"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]