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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?. 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.

ORGANISM(S): Mus musculus

SUBMITTER: Sam Forster

PROVIDER: E-GEOD-48827 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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?.

2013-07-13 | GSE48827 | GEO

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.

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

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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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Microarray analysis of IFN-response

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Tumour cells can escape antiproliferative pressure by type I interferon through immunoediting of interferon receptor expression

Project description:Type I interferons (IFNs) play a central role in innate immunity against virus infection, but also in the antitumour response. In tumour biology, an important mechanism of action apart from the more indirect immune-modulatory and anti-angiogenic effects of IFNs, is their direct impact on cell proliferation. Particularly for cancers arising in the context of chronic inflammation, constant exposure of cells to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of tumour subclones or -populations that developed resistance to the antiproliferative effects of IFN might constitute an important contribution to immunoediting of the tumour leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

2023-11-21 | PXD043761 | Pride

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