Slfn2 Regulates Type I Interferon Responses by Modulating the NFĸB Pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE109991 | GEO | 2018/06/26
REPOSITORIES: GEO
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Project description:Using doxycycline-inducible IFN-kappa expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrate that IFN-kappa inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited 4-6h after IFN-kappa expression. This was also observed with recombinant IFN-beta suggesting a common mechanism of IFNs. RNA-seq analysis identified 1367 IFN-kappa regulated genes of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs confirming that IFN-kappa acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNAi and co-transfection experiments indicate that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-kappa. CIN612-9E/pInd-IFN-kappa were induced for 4h with 1µg/ml doxycyclin or not. Three biological replicates were analyzed.
2015-11-04 | E-GEOD-74658 | biostudies-arrayexpress
Project description:Type I interferons (IFN-I) are critical in antimicrobial and antitumor defense. Although IFN-I signal via the interferon-stimulated gene factor 3 (ISGF3) complex consisting of STAT1, STAT2 and IRF9, IFN-I can mediate significant biological effects via ISGF3-independent pathways. For example, absence of STAT1, STAT2 or IRF9 exacerbates neurological disease in transgenic mice with CNS-production of IFN-gamma. Here we determined the role of IFN-I-driven, ISGF3-independent signaling in regulating global gene expression in STAT1, STAT2 or IRF9-deficient murine mixed glial cell cultures (MGCs). Compared with WT, the expression of IFN-gamma-stimulated genes (ISGs) was reduced in number and magnitude in MGCs that lacked STAT1, STAT2 or IRF9. There were significantly fewer ISGs in the absence of STAT1 or STAT2 versus the absence of IRF9. The majority of ISGs regulated in the STAT1-, STAT2- or IRF9-deficient MGCs individually were shared with WT. However, only a minor number of ISGs were common to WT, STAT1-, STAT2- and IRF9-deficient MGCs. While signal pathway activation in response to IFN-gamma was rapid and transient in WT MGCs, this was delayed and prolonged and correlated with increased numbers of ISGs expressed at 12 h versus 4 h IFN-gamma exposure in all three IFN-I-signaling-deficient MGCs. In conclusion, (1) IFN-I can mediate ISG expression in MGCs via ISGF3-independent signaling pathways but with reduced efficiency, with delayed and prolonged kinetics and is more dependent on STAT1 and STAT2 than IRF9, and (2) signaling pathways not involving STAT1, STAT2 or IRF9 play a minor role only in mediating ISG expression in MGCs.
2017-02-15 | E-MTAB-5445 | biostudies-arrayexpress
Project description:SPT6, encoded by the SUPT6H in humans and Supt6 in mice, respectively, is a conserved histone chaperone that interacts with RNA polymerase II and participates in transcription elongation. However, the question of how SPT6 comes into play in transcriptional activation upon signaling, particularly in mammalian cells, has remained elusive. We investigated the contribution of SPT6 to interferon beta (IFNbeta) induced transcription in mouse NIH3T3 cells. IFNbeta triggers rapid and high level transcription of many IFN-stimulated genes (ISGs). We report here that SPT6 is recruited to ISGs after IFN stimulation. This recruitment was dependent on the interaction with the methyltransferase, NSD2. Further, siRNA-based SPT6 knockdown reduced levels of ISG activation. RNA-Seq analysis showed that SPT6 knockdown diminished about 50% of ISGs whose induction levels were higher than those unaffected by SPT6 knockdown. Under the tested conditions, SPT6 knockdown did not measurably change expression of constitutively expressed genes. This report highlights that SPT6 is recruited in a stimulus-dependent manner and elicits a major impact on signal induced transcription.
2018-05-01 | GSE97302 | GEO
Project description:Using doxycycline-inducible IFN-kappa expression in CIN612-9E cells, which maintain extrachromosomally replicating HPV31 genomes, we demonstrate that IFN-kappa inhibits the growth of these cells and reduces viral transcription and replication. Interestingly, the initiation of viral early transcription was already inhibited 4-6h after IFN-kappa expression. This was also observed with recombinant IFN-beta suggesting a common mechanism of IFNs. RNA-seq analysis identified 1367 IFN-kappa regulated genes of which 221 were modulated >2-fold. The majority of those (71%) matched known ISGs confirming that IFN-kappa acts as a bona fide type I IFN in hr-HPV-positive keratinocytes. RNAi and co-transfection experiments indicate that the inhibition of viral transcription is mainly due to the induction of Sp100 proteins by IFN-kappa.
2015-11-04 | GSE74658 | GEO
Project description:HIV is able to outpace the innate immune response, including the response mediated by interferon (IFN), to establish a productive infection. However, monocyte derived macrophages (MDMs) may be protected from HIV infection by treatment with type I IFN before virus exposure. The ability of HIV to modulate the type I IFN-mediated innate immune response when it encounters a cell that has already been exposed to IFN was investigated. To investigate the presence of HIV on an established IFN response, MDMs were subjected to four different conditions: (1) IFN-treated only, (2) IFN-treated followed by HIV infection, (3) HIV infected only, and (4) a mock-treated and mock-infected control. Microarray gene expression analysis was performed on a total of 24 samples derived from the 4 conditions assessed at 3 time points (1, 4 and 8 days following treatment/infection) for both IFN-α2 or -ω. Initially, ISGs were identified as those that were upregulated greater than 2-fold by IFN alone (condition 1) at both Days 4 and 8. Then, the IFN-treated condition was compared to the IFN-treated followed by HIV-infection condition in order to identify those ISGs that were downregulated at least 1.5-fold by the presence of HIV at both days. Assuming that it would be counterproductive for HIV infection by itself to induce the expression of ISGs with putative anti-HIV effects, those ISGs that were upregulated greater than 2-fold in the HIV control were removed. Finally, ISGs that passed these filters and were concordant with both IFN-treatments (IFN-α2 and -ω) were identified and corresponded to the following 8 ISGs: AXL receptor tyrosine kinase (AXL), interferon-alpha inducible protein 27 (IFI27), interferon-induced protein 44 (IFI44), interferon-induced protein 44-like (IFI44L), ISG15, OAS1, OAS3 and XIAP associated factor 1 (XAF1). It should be noted that the IFN-α2 and -ω microarray experiments were performed in different batches but batch effects were not corrected since genes were identified by the filtering approach just described within each batch.
2013-01-01 | E-GEOD-41731 | biostudies-arrayexpress
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:Slfn2 Regulates Type I Interferon Responses by Modulating the NFĸB Pathway
| PRJNA432533 | ENA
Project description:Methods and Materials The high throughput RNA sequencing (RNA-seq) data from kidney biopsies of LN patients and controls was applied studied to screen for candidate lncRNAs. Quantitative real-time polymerase chain reaction(RT-qPCR) was used to detect the expression of lncRNAs and individual IFN-stimulated genes (ISGs). Western blotting and dual-luciferace luciferase reporter assay was adopted to explore the specific function of the candidate lncRNA. Results The expression of lncRNA RP11-2B6.2 was significantly increased in the kidney tissues from LN patients compared with those from healthy controls, and positive correlated with the degree of disease activity and renal injuryinjuries. Additionally, expression of LncRNA RP11-2B6.2 could be stimulated by type I IFN. Silencing it RP11-2B6.2 significantly reduced the expression of a group of interferon-stimulating genes(ISGs) including IFIT1, OAS1, etc., Furthermore, it lncRNA RP11-2B6.2 affected the expression of IFN alpha and beta receptor subunit 1 (IFNAR1), phosphorylation of Jak1 and Stat1, and the luciferase activity induced by interferon stimulated response element(ISRE). Conclusion Long noncoding RNA RP11-2B6.2 is a positive regulator of the type I IFN signaling pathway in LN. It LncRNA RP11-2B6.2 may contribute to the pathogenesis of LN and provide served as a potentially therapeutic target.
2019-05-01 | GSE98422 | GEO
Project description:Human adenoviruses (HAdV) are a large family of DNA viruses generally infecting the airway, the gut, the eye, and the urinary tract. However, certain strains of HAdVs are capable of causing severe infections in the very young, the elderly, the immunocompromised, and sometimes healthy individuals. In particular, species B HAdVs are often associated with more severe disease, involving serotype 7 and 14. Despite the severity of the disease caused by these strains, little is known about the molecular mechanisms underpinning the disease outcomes. Activation of interferon stimulated genes (ISGs) occurs rapidly after interferon (IFN) stimulation and relies on recruitment of the transcription factor complex IFN-stimulated gene factor 3 (ISGF3) to promoters, which happens via the canonical JAK-STAT pathway. Therefore, suppression of IFNs is a key aspect of evading innate immunity by viral pathogens, including HAdVs; and as such, HAdVs have evolved multiple ways by which they suppress activation of ISGs in order to drive viral replication. Our previous work investigated the molecular mechanism of interferon suppression by HAdV-C5. We observed that E1A of HAdV-C5 interacts with the AAA+ DNA helicase RuvBL1/Pontin in order to suppress activation of interferon stimulated genes (ISGs) during infection. We therefore wanted to determine whether RuvBL1 is also a target for the more highly pathogenic HAdV-B7 and B14. As part of this investigation, we examined the broad-range effect of HAdV species C2, B7, and B14 on cells in response to interferon. These results are presented here.
2024-06-26 | PXD045673 | Pride
Project description:Type I IFN induces IFN stimulated genes (ISGs) and exert varieties of immunomoduratory functions. However, it is not well characterized how ISGs are regulated by negative regulators of IFN signaling. Here, we analyzed the transcriptomic data when combined with depletion of USP18, one of major negative regulators for IFN signaling.
2022-11-09 | GSE165428 | GEO