Meyer, Thomas J.

[["dc.bibliographiccitation.artnumber","42"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell Communication and Signaling"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Menon, Priyanka R."],["dc.contributor.author","Staab, Julia"],["dc.contributor.author","Gregus, Anke"],["dc.contributor.author","Wirths, Oliver"],["dc.contributor.author","Meyer, Thomas"],["dc.date.accessioned","2022-05-02T08:09:26Z"],["dc.date.accessioned","2022-08-18T12:36:44Z"],["dc.date.available","2022-05-02T08:09:26Z"],["dc.date.available","2022-08-18T12:36:44Z"],["dc.date.issued","2022-03-31"],["dc.date.updated","2022-07-29T12:17:28Z"],["dc.description.abstract","Background\r\nUnphosphorylated signal transducer and activator of transcription 1 (U-STAT1) has been reported to elicit a distinct gene expression profile as compared to tyrosine-phosphorylated STAT1 (P-STAT1) homodimers. However, the impact of U-STAT1 on the IFNγ-induced immune response mediated by P-STAT1 is unknown. By generating a double mutant of STAT1 with mutation R602L in the Src-homology 2 (SH2) domain and Y701F in the carboxy-terminal transactivation domain mimicking U-STAT1, we investigated the effects of U-STAT1 on P-STAT1-mediated signal transduction.\r\n\r\nResults\r\nIn this study, we discovered a novel activity of U-STAT1 that alters the nucleo-cytoplasmic distribution of cytokine-stimulated P-STAT1. While the dimerization-deficient mutant R602L/Y701F was not able to display cytokine-induced nuclear accumulation, it inhibited the nuclear accumulation of co-expressed IFNγ-stimulated wild-type P-STAT1. Disruption of the anti-parallel dimer interface in the R602L/Y701F mutant via additional R274W and T385A mutations did not rescue the impaired nuclear accumulation of co-expressed P-STAT1. The mutant U-STAT1 affected neither the binding of co-expressed P-STAT1 to gamma-activated sites in vitro, nor the transcription of reporter constructs and the activation of STAT1 target genes. However, the nuclear accumulation of P-STAT1 was diminished in the presence of mutant U-STAT1, which was not restored by mutations reducing the DNA affinity of mutant U-STAT1. Whereas single mutations in the amino-terminus of dimerization-deficient U-STAT1 similarly inhibited the nuclear accumulation of co-expressed P-STAT1, a complete deletion of the amino-terminus restored cytokine-stimulated nuclear accumulation of P-STAT1. Likewise, the disruption of a dimer-specific nuclear localization signal also rescued the U-STAT1-mediated inhibition of P-STAT1 nuclear accumulation.\r\n\r\nConclusion\r\nOur data demonstrate a novel role of U-STAT1 in affecting nuclear accumulation of P-STAT1, such that a high intracellular concentration of U-STAT1 inhibits the detection of nuclear P-STAT1 in immunofluorescence assays. These observations hint at a possible physiological function of U-STAT1 in buffering the nuclear import of P-STAT1, while preserving IFNγ-induced gene expression. Based on these results, we propose a model of a hypothetical import structure, the assembly of which is impaired under high concentrations of U-STAT1. This mechanism maintains high levels of cytoplasmic STAT1, while simultaneously retaining signal transduction by IFNγ."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.citation","Cell Communication and Signaling. 2022 Mar 31;20(1):42"],["dc.identifier.doi","10.1186/s12964-022-00841-3"],["dc.identifier.pii","841"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/107378"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112955"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-561"],["dc.publisher","BioMed Central"],["dc.relation.eissn","1478-811X"],["dc.rights","CC BY 4.0"],["dc.rights.holder","The Author(s)"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","STAT1"],["dc.subject","JAK-STAT signalling"],["dc.subject","Dimerization"],["dc.subject","Nuclear accumulation"],["dc.subject","Interferon-induced gene expression"],["dc.title","An inhibitory effect on the nuclear accumulation of phospho-STAT1 by its unphosphorylated form"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]