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Structural basis of a novel Interferon b signaling axis mediated via the ifnar1 receptor

ABSTRACT: Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?.

ORGANISM(S): Mus musculus

PROVIDER: GSE48827 | GEO | 2013/07/13

SECONDARY ACCESSION(S): PRJNA211861

REPOSITORIES: GEO

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Structural basis of a novel Interferon b signaling axis mediated via the ifnar1 receptor

Project description:Type I interferons (IFNs) are a family of cytokines that play an important role in regulating immune responses to pathogens and tumors and are used therapeutically. All IFNs are considered to signal via the heterodimeric IFNAR1-IFNAR2 complex, yet some subtypes such as IFN? can exhibit distinct functional properties, although the molecular basis of this is unclear. Here we demonstrate IFN uniquely and specifically ligates to IFNAR1 in an IFNAR2-independent manner and provide the structural basis of the IFNAR1-IFN interaction. We show that the IFNAR1-IFN complex transduces signals to modulate the expression of a set of genes independently of IFNAR2. Moreover, we show the in vivo importance of the IFNAR1-IFN signaling axis in a murine model of LPS-induced septic shock. Thus, we provide a molecular basis for understanding specific functions of IFN?. Interferon b induced gene expression in peritoneal exudate cells was measured 3hr post intra-peritoneal injection of 10,000IU/ml of interferon beta or saline into wildtype and Ifnar2-/- mice. Three independant experiments were performed for each treatment in both genotypes using different mice for each sample.

2013-07-13 | E-GEOD-48827 | biostudies-arrayexpress

Synthetic mimetics assigned a major role to IFNAR2 in type I Interferon signaling

Project description:Type I Interferons (IFNs) are potent inhibitors of viral replication. Here, we reformatted the natural murine and human type I Interferon-α/β receptors IFNAR1 and IFNAR2 into fully synthetic biological switches. The transmembrane and intracellular domains of natural IFNAR1 and IFNAR2 were conserved, whereas the extracellular domains were exchanged by nanobodies directed against the fluorescent proteins Green fluorescent protein (GFP) and mCherry. Using this approach, multimeric single-binding GFP-mCherry ligands induced synthetic IFNAR1/IFNAR2 receptor complexes and initiated STAT1/2 mediated signal transduction via Jak1 and Tyk2. Homodimeric GFP and mCherry ligands showed that IFNAR2 but not IFNAR1 homodimers were sufficient to induce sustained STAT1/2 signaling. Transcriptome analysis revealed that synthetic murine type I IFN signaling was highly comparable to IFNα4 signaling and resulted in efficient elimination of vesicular stomatitis virus (VSV) in a cell culture based viral infection model using MC57 cells stimulated with synthetic type IFN ligands. Using intracellular deletion variants and point mutations, Y510 and Y335 in murine IFNAR2 were verified as unique phosphorylation sites for STAT1/2 activation, whereas the other tyrosine residues in IFNAR1 and IFNAR2 were not involved in STAT1/2 phosphorylation. Comparative analysis of synthetic human IFNARs supporting this finding. In summary, our data showed that synthetic type I IFN signal transduction is originating from IFNAR2 rather than IFNAR1.

2022-09-21 | GSE202839 | GEO

Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

Project description:Type I interferon (IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to regulate sterile and infectious immunity. IFNAR1 expression is tightly regulated to prevent autoimmunity although the mechanisms governing this are incompletely understood. We investigated the strategies used by two flaviviruses, tick-borne encephalitis virus and West Nile virus, to antagonize IFN-I signaling. Infection with these viruses resulted in depletion of IFNAR1 associated with the function of the viral IFN-I antagonist, NS5. NS5 function was dependent on its ability to associate with prolidase (PEPD), a cellular dipeptidase. PEPD was required for IFNAR1 maturation and accumulation, as well as gene induction following IFNAR1 stimulation. The relevance of PEPD to human biology was confirmed in fibroblasts derived from patients with genetic prolidase deficiency that expressed low IFNAR1 and exhibited reduced responses to IFNAR1. Thus, by understanding flavivirus IFN-I antagonism, PEPD is revealed as a central regulator of IFN-I responses in humans. RNA was isolated from replicates of 4 cultured dermal fibroblast lines derived from patients with genetic prolidase deficiency (PEPD), as well as from 4 cultured dermal fibroblast lines derived from normal healthy donors. These were run on Agilent microarrays to compare differences in gene expression observed in PEPD fibroblasts compared with normal fibroblasts.

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Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 trafficking and expression

2015-07-08 | GSE64387 | GEO

ISG induction in ∆7bp IFNAR2 mutant, IFNAR1 KO and wild type THP1.

Project description:ISG induction in IFNAR2 mutant, IFNAR1 KO and wild type THP1

2023-01-25 | GSE211502 | GEO

Whole transcriptome shotgun sequencing of type 1 IFN key proteins knock out clones

Project description:Purpose: Describe the contribution of the receptor parts IFNAR1 and IFNAR2 as well as STAT1 and STAT2 proteins to type 1 IFN signaling pathway.

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Project description:To clarify the role of interferon regulatory factor 5 (IRF5) other than inducing type I interferons (IFNs) in the pathogenesis of systemic lupus erythematosus (SLE), we performed transcriptome analysis of peripheral blood from Lyn-deficient mice with concomitant Ifnar1 or Irf5 deficiency. The results of gene set enrichment analysis (GSEA) suggest that IRF5 is involved in the induction of not only IFN-inducible genes (ISGs) but also oxidative phosphorylation (OXPHOS)-related genes in the SLE pathogenesis.

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Gene expression analysis of intestinal stem cells (ISCs) from polyI:C treated WT mice or Ifnar1-/- mice.

Project description:To explore the influence of IFNR-mediated singnaling in ISCs, we performed microarray analysis of the ISCs from control Lgr5ki mice versus Ifnar1-/-Lgr5ki mice after treating for 1 weeks with low doses of poly(I:C), which potentially induce type I and -III IFNs. The Gene Ontology (GO) analysis indicated that the GO terms overrepresented among the genes upregulated in ISCs from poly(I:C)-treated WT mice compared with those from poly(I:C)-treated Ifnar1−/− mice included “defense response to virus”, “immune system process”, “response to virus”, and “innate immune response”, all from the GOTERM_Biological Processes (BP) category. We compared these results against the Interferome database, which contains genes regulated by type I, II, or III IFN, compiled by analyzing the expression data of IFN-treated cells (http://www.interferome.org), and found that most of the genes found for the GO term “defense response to virus” were IFN-inducible genes, indicating that IFNs act directly on ISCs. The GO analysis also showed an enrichment of defense response to bacteria. In the GOTERM_Cellular Component (CC) category, “extracellular space” and “extracellular region” ranked at the top, indicating a dramatic change in the expression pattern of secretory molecules. Notably, these GO terms included genes encoding antibacterial proteins and endocrine hormones such as angiogenin, defensin, lysozyme, chromogranin, and glucagon, all of which are produced by secretory IECs. Thus, we hypothesized that excess IFN signals force ISCs to lose stemness and differentiate into secretory progenitors.

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Project description:Inhibition of IFN-I signaling promotes the control of persistent virus infection, but the underlying mechanisms remain poorly understood. Here we report that genetic ablation of IFNAR1 specifically in NK cells led to elevated numbers of T follicular helper cells, germinal center B cells, and plasma cells, resulting in hastened virus clearance comparable to IFNAR1 blockade by an IFNAR1 neutralizing antibody. Antigen-specific B cells and antiviral antibodies were essential for the accelerated control of LCMV Cl13 infection following IFNAR1 blockade. IFNAR1 signaling in NK cells promoted NK cell maturation, function, and killing of antigenspecific CD4 and CD8 T cells. Therefore, Inhibition of IFN I signaling in NK cells enhances CD4 and CD8 T cell responses, elevates humoral immune response, and thereby facilitates the control of persistent virus infection.

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2024-05-28 | PXD045482 | Pride

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