Threonine Phosphorylation of STAT1 Restricts Interferon Signaling and Promotes Innate Inflammatory Responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1089167 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28375571.fastq.gz | Fastqsanger.gz | |||
| SRR28375572.fastq.gz | Fastqsanger.gz | |||
| SRR28375573.fastq.gz | Fastqsanger.gz | |||
| SRR28375574.fastq.gz | Fastqsanger.gz | |||
| SRR28375575.fastq.gz | Fastqsanger.gz |
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Project description:Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr748 as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically-engineered mice expressing phospho-deficient threonine748–to-alanine (T748A) mutant Stat1 are resistant to LPS–induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point-mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase (IKK)–mediated Thr748 phosphorylation of Stat1, which promotes macrophages inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent functional dichotomy of Stat1 in innate immune responses: IFN phospho-tyrosine dependent, and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover novel pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.
2024-03-18 | GSE261824 | GEO
Project description:Uncontrolled inflammation drives tissue damage, highlighting the need for tightly regulated immune responses and tissue integrity, particularly in barrier tissues like the intestine. To maintain this exquisite balance, intestinal epithelial cells (IECs) employ molecular circuits that preserve tissue integrity following inflammation. STAT1 is traditionally viewed as a pro-inflammatory driver in the intestine, acting as a central signaling mediator downstream of interferons (IFN). Here, we identify threonine 748 (Thr748) phosphorylation of Stat1 as an evolutionarily conserved adaptation that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe pathology similar to Stat1 deficient littermates, underscoring Thr748’s critical role in Stat1-driven protection following intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is non-hematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates Stat1 DNA binding, directly activating the Itgb4 promoter and enhancing integrin β4 expression in IECs following inflamamtion. In vitro intestinal organoid models, combined with gain- and loss-of-function experiments, show that Stat1 promotes integrin β4 expression via Thr748 phosphorylation following damage, boosting epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation triggers Tyr701 phosphorylation of Stat1, upregulating Zbp1—a sensor of cytotoxic damage-associated nucleic acids—while suppressing integrin β4, leading to epithelial cytotoxicity, which is mitigated by Thr748 phosphorylation. Our findings uncover a modular architecture of Stat1 signaling that enables epithelial adaptation to damage, with Thr748 phosphorylation acting as a rheostat to preserve tissue integrity while restricting IFN-mediated cytotoxicity.
2025-07-09 | GSE297456 | GEO
Project description:Uncontrolled inflammation drives tissue damage, highlighting the need for tightly regulated immune responses and tissue integrity, particularly in barrier tissues like the intestine. To maintain this exquisite balance, intestinal epithelial cells (IECs) employ molecular circuits that preserve tissue integrity following inflammation. STAT1 is traditionally viewed as a pro-inflammatory driver in the intestine, acting as a central signaling mediator downstream of interferons (IFN). Here, we identify threonine 748 (Thr748) phosphorylation of Stat1 as an evolutionarily conserved adaptation that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe pathology similar to Stat1 deficient littermates, underscoring Thr748’s critical role in Stat1-driven protection following intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is non-hematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates Stat1 DNA binding, directly activating the Itgb4 promoter and enhancing integrin β4 expression in IECs following inflamamtion. In vitro intestinal organoid models, combined with gain- and loss-of-function experiments, show that Stat1 promotes integrin β4 expression via Thr748 phosphorylation following damage, boosting epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation triggers Tyr701 phosphorylation of Stat1, upregulating Zbp1—a sensor of cytotoxic damage-associated nucleic acids—while suppressing integrin β4, leading to epithelial cytotoxicity, which is mitigated by Thr748 phosphorylation. Our findings uncover a modular architecture of Stat1 signaling that enables epithelial adaptation to damage, with Thr748 phosphorylation acting as a rheostat to preserve tissue integrity while restricting IFN-mediated cytotoxicity.
2025-07-09 | GSE297455 | GEO
Project description:Threonine Phosphorylation of STAT1 Safeguards Gut Epithelial Integrity and Restricts Interferon-mediated Cytotoxicity [ChIP-seq]
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Project description:Threonine Phosphorylation of STAT1 Safeguards Gut Epithelial Integrity and Restricts Interferon-mediated Cytotoxicity [RNA-seq]
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Project description:Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr748 as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr748 phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.
| S-EPMC11046697 | biostudies-literature
Project description:Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target genes activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P and this interaction facilitates the recruitment of the SET1/MLL complex and subsequent H3K4 trimethylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a six-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knock-down or chemical inhibition severely blocks WDR5 association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation, and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and a major driver of androgen-dependent prostate cancer cell proliferation. Identification of Histone 3 threonine 11 phosphorylation (H3T11P) marks and WDR5 binding sites in LNCaP cells treated with R1881 ligand (androgen) or solvent control.
2014-07-01 | E-GEOD-55279 | biostudies-arrayexpress
Project description:Serine/Threonine Phosphorylation of RUNX1 Promotes Megakaryocytic Fate in Megakaryocyte-Erythroid Progenitors
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Project description:Stringent regulation of the interferon signaling pathway is essential for maintaining the immune response to pathogens and tumors. The transcription factor STAT1 is a crucial mediator of this response. Here we show that hCAF1/CNOT7 regulates class I and II interferon pathways at different crucial steps. In resting cells hCAF1 can control STAT1 trafficking by interacting with the latent form of STAT1 in the cytoplasm. IFN treatment induces STAT1 release, suggesting that hCAF1 may shield cytoplasmic STAT1 from undesirable stimulation. Consistent, hCAF1 silencing enhances STAT1 basal promoter occupancy associated with increased expression of a subset of STAT1-regulated genes. Consequently, hCAF1 knockdown cells exhibit an increased protection against viral infection and reduced viral replication. Furthermore, hCAF1 participates in the extinction of the IFN signal, through its deadenylase activity, by speeding up the degradation of some STAT1-regulated mRNAs. Since abnormal and unbalanced JAK/STAT activation is associated with immune disorders and cancer, hCAF1 could play a major role in innate immunity and oncogenesis, contributing to tumor escape. mRNAs from cells expressing the siRNA siRNA duplexes targeting hCAF1, corresponding to the coding region 941-961 (kd) (hCAF1 NCBI Reference Sequence: NM_013354.5) and one non-targeting control siRNA (mock).
2013-12-31 | E-GEOD-43334 | biostudies-arrayexpress
Project description:We used ChIP-seq to determine the whole-genome enrichment of histone H3 threonine 11 phosphorylation (H3 T11ph) during Saccharomyces cerevisiae meiosis. S. cerevisiae SK1 cells were synchronized for meiotic entry and 3 and 4 hour meiotic samples were obtained. As H3 T11ph is dependent on the formation of meiotic double strand breaks (DSBs), a negative control ChIP-seq sample was obtained from a strain lacking DSBs (spo11-yf). Concurrently, ChIP-seq was carried out for histone H3 as a control for comparision.
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