Phosphorylation of human interferon regulatory factor 9
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Velos Pro
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Siew Kit Ng
PROVIDER: MSV000089924 | MassIVE | Wed Jul 20 02:10:00 BST 2022
SECONDARY ACCESSION(S): PXD035428
REPOSITORIES: MassIVE
Similar Datasets
Project description:Activation of the TLR4 signaling pathway by LPS leads to induction of both inflammatory and interferon-stimulated genes, however, the mechanisms through which these coordinately activated transcriptional programs are balanced to promote an optimal innate immune response remain poorly understood. In a genome-wide siRNA screen of the LPS-induced TNF- response in macrophages, we identified the interferon-stimulated protein IFIT1 as a negative regulator of the inflammatory gene program. Transcriptional profiling further identified an unexpected positive regulatory role for IFIT1 in type I interferon expression, implicating IFIT1 as a reciprocal modulator of LPS-induced gene classes. We demonstrate that these effects of IFIT1 are mediated through modulation of a Sin3A-HDAC2 transcriptional regulatory complex at LPS-induced gene loci. Beyond the well-studied role of cytosolic IFIT1 in restricting viral replication, our data demonstrate an unappreciated function for nuclear IFIT1 in differential transcriptional regulation of separate branches of the LPS-induced gene program.
2018-09-10 | GSE103829 | GEO
Project description:Host defense by the innate immune system requires the establishment of antimicrobial states allowing cells to cope with microorganisms before the onset of the adaptive immune response. Interferons (IFN) are of vital importance in the establishment of cell-autonomous antimicrobial immunity. Speed is therefore an important attribute of the cellular response to IFN. With much of the antimicrobial response being installed de novo, this pertains foremost to gene expression, the rapid switch between resting-state and active-state transcription of host defense genes. Mechanisms to meet this demand on the relevant molecular machinery include remodeling of chromatin but also changes in transcription factor interaction prior and during the IFN response. Our results show how distinct transcription factor complexes, determine the responsiveness of Interferon stimulated genes to different IRF9-containing complexes. Raw 264.7 macrophages expressing a doxycycline-inducible, myc-tagged versions of each IRF9-BirA*, STAT2-BirA* and STAT1-BirA* fusion genes were used to study complex formation in vivo. Furthermore, we extended the BioID proximity labeling by coupling it to parallel reaction monitoring to determine the degree and quantity of association between IRF9 and STATs in resting and interferon-treated macrophages.
2019-07-03 | PXD013209 | Pride
Project description:Interferon regulatory factor 5 (IRF5) plays a distinct role in the regulation of immune responses in health and disease and is a genetic risk factor several autoimmune conditions, including systemic lupus erythematosus, diabetes, arthritis and inflammatory bowel disease. IRF5 function as a transcription factor requires post-translational modifications of the protein such as phosphorylation. Though several upstream signalling regulators of IRF5 have been identified, there is as yet little understanding of how they control IRF5 activity or whether other unknown kinases are involved. In this study, we systematically searched for IRF5 kinases using a reporter-based method for screening a library of 365 inhibitors of protein kinases. Based on the pool of the identified IRF5-inhibiting compounds we have compiled a list of putative IRF5 kinases, which we tested in subsequent in vitro assays. Protein-tyrosine kinase 2-beta (Ptk2b or PYK2) was one of the top hits, capable of binding to and phosphorylating mouse IRF5 at tyrosine (Y) 171. We have shown that IRF5 recruitment to target genes and IRF5-dependent transcription was impaired in cells treated with highly selective PYK2 inhibitors or in PYK2-deficient cells. Moreover, expression of pro-inflammatory cytokines was blocked in the supernatants of human biopsies from inflamed colon of patients with ulcerative colitis and treated ex vivo with a PYK2 inhibitor. Thus, we have identified a major role for PYK2 in regulating the inflammatory response and mapped its activity to the IRF5 innate sensing pathways.
2021-10-14 | PXD014033 | Pride
Project description:Host defense by the innate immune system requires the establishment of antimicrobial states allowing cells to cope with microorganisms before the onset of the adaptive immune response. Interferons (IFN) are of vital importance in the establishment of cell-autonomous antimicrobial immunity.
Speed is therefore an important attribute of the cellular response to IFN. With much of the antimicrobial response being installed de novo, this pertains foremost to gene expression, the rapid switch between resting-state and active-state transcription of host defense genes. Mechanisms to meet this demand on the relevant molecular machinery include remodeling of chromatin but also changes in transcription factor interaction prior and during the IFN response.
Our results show how distinct transcription factor complexes, determine the responsiveness of Interferon stimulated genes to different IRF9-containing complexes. Raw 264.7 macrophages expressing a doxycycline-inducible, myc-tagged versions of each IRF9-BirA*, STAT2-BirA* and STAT1-BirA* fusion genes were used to study complex formation in vivo. Furthermore, we extended the BioID proximity labeling by coupling it to parallel reaction monitoring to determine the degree and quantity of association between IRF9 and STATs in resting and interferon-treated macrophages.
2019-07-15 | PXD013251 | panorama
Project description:Peste des petits ruminants virus (PPRV) infection causes highly contagious and severe disease in domestic and wild ruminants. It is widely reported that PRRV infection causes considerable innate immunosuppression in its host and promotes viral replication. However, how does the host rescue the innate immune response to counteract this immunosuppression during viral replication is poorly understood. The goat fetal fibroblasts (GFFs) have been commonly used as host-original cells to investigate the pathogenesis of PPRV. To explore the mechanisms of how host counteracts PPRV-mediated innate immunosuppression, a high-throughput quantitation proteomic approach (iTRAQ in conjunction with LC-MS/MS) was used to investigate the proteome landscape of GFFs in response to PPRV infection. Eventually, the proteomic analysis gained 497 up-regulated proteins and 358 down-regulated proteins (PPRV-infected cells versus mock-infected cells). The complement and coagulation cascades, protein digestion and absorption, and cytokine-cytokine receptor interaction pathways were significantly regulated in response to PPRV infection. ErmineJ analysis of the differentially expressed proteins (DEPs) identified the significantly enriched GO categories for response to interferon-gamma and positive regulation of ERK1 and ERK2 cascade. In addition, many immune related proteins, such as interferon gamma, 2'-5'-oligoadenylate synthase-like protein, toll-like receptor 9, toll-like receptor 6, NOD1, plasminogen activator inhibitor 1, and Wnt-5a were significantly upregulated. This suggested that the innate immune response was triggered during PPRV infection in GFFs. We subsequently identified that the E3 ubiquitin ligase FANCL was critically involved in regulation of the innate immune response during PPRV infection. FANCL inhibited PPRV infection by enhancing type I interferon (IFN) and interferon-stimulated genes (ISGs) expression. Further study indicated that FANCL induced type I IFN production by promoting TBK1 phosphorylation, and therefore impairing PPRV-mediated immunosuppression and revealing an antiviral function against PPRV.
2021-07-26 | PXD022271 | Pride
Project description:We found that Interferon Regulatory Factor 7 (IRF7) is upregulated in adipose-derived stromal cells (MSC) of 12 months-old (middle-age) mice compared with 1 month-old mice. To go in depth into the role of IRF7 in aging of MSC we knocked-down it in 12 months MSC and assessed the transcriptional changes though whole-genome microarray analysis. We investigated the transcriptional changes induced by the Interferon Regulatory Factor 7 (IRF7) knock-down in mesenchymal stromal cells established from the inguinal fat pad of 12-months-old mice.
2021-03-10 | GSE168533 | GEO
Project description:Interferon Regulatory Factor 8 (IRF8) Deficiency Promotes Osteoclast Transcriptional Program
| PRJNA475210 | ENA
Project description:The type I interferon (IFN) response protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to map IFN-induced rearrangements in the human protein-protein interaction network. Specifically, we analyzed the IFN-induced changes to the HeLa cell proteome with shotgun mass spectrometry. As well, we assessed the IFN-induced interactome with protein correlation profiling coupled to size exclusion chromatography and SILAC. Finally, we utilized label-free quantitative mass spectrometry for affinity purification mass spectrometry of candidate proteins and to analyze the ribosomal protein composition.
2020-05-15 | PXD013809 | Pride
Project description:Intestinal epithelial cells (IECs) form a primary barrier against microbial invasion. Prior studies of enteric pathogens have indicated that IEC defense mechanisms are distinct from those of other cell types. For example, antiviral defense of IECs depends on type III interferon whereas most cell types depend on type I IFN. Interferon regulatory factors (IRFs) are a family of transcription factors with well-described roles in stimulation of IFN cytokines, but IRF6 is unique in its preferential expression by epithelial lineages. IRF6 has primarily been studied in epidermal development, but has relatively unknown roles in the intestinal epithelium. Here, we found that Irf6 KO regulated IFN-stimulated antiviral immunity of IECs but had no effect on macrophages. RNseq analysis of Irf6 KO cells showed significant differences in the IFN-stimulated gene expression program that correlated with the magnitude of antiviral gene stimulation. We also found significant baseline phenotypic and transcriptional changes in Irf6 KO IECs, with reduced rate of growth and preturbation of growth and differentiation pathway genes. Knockout of Irf6 in primary IEC organoids also resulted in slower growth and smaller size. Transcriptional analysis of Irf6 KO organoids indicated reduced expression of genes in the epithelial differentiation pathwya, including Wnt and Notch pathway genes, as well as increased expression of a subset of IFN-stimulated genes. These data indicate a previously unappreciated role of Irf6 in shaping the IEC transcriptome, including baseline epithelial development genes and IFN-stimulated genes.
2023-11-01 | GSE245971 | GEO
Project description:Intestinal epithelial cells (IECs) form a primary barrier against microbial invasion. Prior studies of enteric pathogens have indicated that IEC defense mechanisms are distinct from those of other cell types. For example, antiviral defense of IECs depends on type III interferon whereas most cell types depend on type I IFN. Interferon regulatory factors (IRFs) are a family of transcription factors with well-described roles in stimulation of IFN cytokines, but IRF6 is unique in its preferential expression by epithelial lineages. IRF6 has primarily been studied in epidermal development, but has relatively unknown roles in the intestinal epithelium. Here, we found that Irf6 KO regulated IFN-stimulated antiviral immunity of IECs but had no effect on macrophages. RNseq analysis of Irf6 KO cells showed significant differences in the IFN-stimulated gene expression program that correlated with the magnitude of antiviral gene stimulation. We also found significant baseline phenotypic and transcriptional changes in Irf6 KO IECs, with reduced rate of growth and preturbation of growth and differentiation pathway genes. Knockout of Irf6 in primary IEC organoids also resulted in slower growth and smaller size. Transcriptional analysis of Irf6 KO organoids indicated reduced expression of genes in the epithelial differentiation pathwya, including Wnt and Notch pathway genes, as well as increased expression of a subset of IFN-stimulated genes. These data indicate a previously unappreciated role of Irf6 in shaping the IEC transcriptome, including baseline epithelial development genes and IFN-stimulated genes.
2023-11-01 | GSE245970 | GEO