Nast, Roswitha

[["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","45"],["dc.bibliographiccitation.journal","Experimental Parasitology"],["dc.bibliographiccitation.lastpage","54"],["dc.bibliographiccitation.volume","180"],["dc.contributor.author","Sumpf, Kristina"],["dc.contributor.author","Nast, Roswitha"],["dc.contributor.author","Downie, Bryan R."],["dc.contributor.author","Salinas, Gabriela"],["dc.contributor.author","Lüder, Carsten G. K."],["dc.date.accessioned","2019-08-07T07:23:22Z"],["dc.date.available","2019-08-07T07:23:22Z"],["dc.date.issued","2017"],["dc.description.abstract","Toxoplasma gondii is a ubiquitous apicomplexan parasite of mammals and birds and an important pathogen of humans. IFN-γ is the major mediator of host resistance against T. gondii but intriguingly, parasite-infected host cells including macrophages are severely impaired to respond to IFN-γ due to defective transcriptional activation of target genes. Here, we tested the possibility that the impaired responsiveness of T. gondii-infected macrophages to IFN-γ can be restored by inhibiting histone deacetylases (HDACs) using the class I-specific inhibitor MS-275. Treatment of RAW264.7 cells with MS-275 indeed increased MHC class II surface expression in infected and non-infected cells and largely abolished the inhibition of IFN-γ-regulated MHC class II expression exerted by T. gondii. Genome-wide transcriptome profiling revealed that MS-275 increased mean mRNA levels of IFN-γ-regulated genes particularly in non-infected macrophages. Transcript levels of 33% of IFN-γ secondary response genes but only those of a few primary response genes were also increased by MS-275 in T. gondii-infected cells. Importantly, the unresponsiveness of parasite-infected cells to IFN-γ was however not abolished by MS-275. Furthermore, MS-275 also up-regulated several anti-inflammatory cytokines or signaling molecules in T. gondii-infected macrophages. It additionally regulated expression of more than 2500 genes in non-infected macrophages expression of which was surprisingly counteracted by prior infection with T. gondii. FACS analysis and immunofluorescence microscopy revealed that MS-275 did not considerably diminish the number of parasite-positive cells or the intracellular replication in macrophages stimulated or not with IFN-γ. Thus, a supportive therapy using MS-275 appears inappropriate for treatment of toxoplasmosis."],["dc.identifier.doi","10.1016/j.exppara.2017.02.011"],["dc.identifier.pmid","28189488"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62330"],["dc.language.iso","en"],["dc.relation.eissn","1090-2449"],["dc.relation.issn","0014-4894"],["dc.title","Histone deacetylase inhibitor MS-275 augments expression of a subset of IFN-γ-regulated genes in Toxoplasma gondii-infected macrophages but does not improve parasite control"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["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"]]

[["dc.bibliographiccitation.firstpage","456"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Trends in Parasitology"],["dc.bibliographiccitation.lastpage","459"],["dc.bibliographiccitation.volume","31"],["dc.contributor.author","Lueder, Carsten Guenter Kurt"],["dc.contributor.author","Sumpf, Kristina"],["dc.contributor.author","Nast, Roswitha"],["dc.date.accessioned","2018-11-07T09:50:52Z"],["dc.date.available","2018-11-07T09:50:52Z"],["dc.date.issued","2015"],["dc.identifier.doi","10.1016/j.pt.2015.08.006"],["dc.identifier.isi","000363077200003"],["dc.identifier.pmid","26422772"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35795"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Sci Ltd"],["dc.relation.issn","1471-5007"],["dc.relation.issn","1471-4922"],["dc.title","Releasing the Brake on IFN-gamma Signaling on Infection"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.subtype","letter_note"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Immunology"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Nast, Roswitha"],["dc.contributor.author","Choepak, Tenzin"],["dc.contributor.author","Lüder, Carsten G. K."],["dc.date.accessioned","2021-04-14T08:32:39Z"],["dc.date.available","2021-04-14T08:32:39Z"],["dc.date.issued","2020"],["dc.description.abstract","Host defense against the human pathogen Toxoplasma gondii depends on secretion of interferon (IFN)-γ and subsequent activation of monocytic cells to combat intracellular parasites. Previous studies have shown that T. gondii evades IFN-γ-mediated immunity by secreting the effector TgIST into the host cell where it binds to STAT1, strengthens its DNA binding activity and recruits the Mi-2/NuRD complex to STAT1-responsive promoters. Here we investigated the impact of the host chromatin environment on parasite interference with IFN-γ-induced gene expression. Luciferase reporters under control of primary and secondary IFN-γ response promoters were only inhibited by T. gondii when they were stably integrated into the host genome but not when expressed from a plasmid vector. Absence of CpG islands upstream and/or downstream of the transcriptional start site allowed more vigorous up-regulation by IFN-γ as compared to CpG-rich promoters. Remarkably, it also favored parasite interference with IFN-γ-induced gene expression indicating that nucleosome occupancy at IFN-γ-responsive promoters is important. Promoter DNA of IFN-γ-responsive genes remained largely non-methylated in T. gondii-infected cells, and inhibition of DNA methylation did not impact parasite interference with host responses. IFN-γ up-regulated histone marks H4ac, H3K9ac, and H3K4me3 but down-regulated H3S10p at primary and secondary response promoters. Infection with T. gondii abolished histone modification, whereas total nuclear activities of histone acetyl transferases and histone deacetylases were not altered. Taken together, our study reveals a critical impact of the host chromatin landscape at IFN-γ-activated promoters on their inhibition by T. gondii with a comprehensive blockade of histone modifications at parasite-inactivated promoters."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2020"],["dc.identifier.doi","10.3389/fimmu.2020.581241"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17577"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83974"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-3224"],["dc.rights","CC BY 4.0"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Epigenetic Control of IFN-γ Host Responses During Infection With Toxoplasma gondii"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1023"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Immunology and Cell Biology"],["dc.bibliographiccitation.lastpage","1025"],["dc.bibliographiccitation.volume","96"],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Nast, Roswitha"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2019-08-07T07:35:01Z"],["dc.date.available","2019-08-07T07:35:01Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1111/imcb.12198"],["dc.identifier.pmid","30246277"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62333"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1440-1711"],["dc.relation.issn","0818-9641"],["dc.title","Do the two transcription factors form a positive feedback amplifier circuit in their common fight against pathogens?"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]