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Results for “interferon signaling”

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At least 19 recordsLinked to original sources

PubMed1995

Transcription factors in interferon signaling.

Interferons (IFNs) comprise a family of polypeptides that exhibit diverse biological effects such as inhibition of cell growth and protection against viral infection. These activities are based mainly on the transcriptional induction of cellular genes by both type I (IFN-alpha and IFN-beta) and type II (IFN-gamma) interferons. Several of these IFN-induced early response genes have been cloned and common elements within their promoters defined. Transcription factors, such as interferon-stimulated gene factor-3, IFN-gamma activation factor and FcRF gamma, that bind to these enhancers subsequently have been isolated and their components identified. This review shall provide an overview of the DNA response elements, the components of the IFN-induced transcription factors and their mechanism of action.

Base Sequence↗

PubMed2004

Host evasion by emerging paramyxoviruses: Hendra virus and Nipah virus v proteins inhibit interferon signaling.

Interferon (IFN) can activate Signal Transducer and Activator of Transcription (STAT) proteins to establish a cellular antiviral response and inhibit virus replication. Many viruses have evolved strategies to inhibit this antiviral mechanism, but paramyxoviruses are unique in their abilities to directly target the IFN-responsive STAT proteins. Hendra virus and Nipah virus (Henipaviruses) are recently emerged paramyxoviruses that are the causative agents of fatal disease outbreaks in Australia and peninsular Malaysia. Similar to other paramyxoviruses, Henipaviruses inhibit IFN signal transduction through a virus-encoded protein called V. Recent studies have shown that Henipavirus V proteins target STAT proteins by inducing the formation of cytoplasmically localized high molecular weight STAT-containing complexes. This sequestration of STAT1 and STAT2 prevents STAT activation and blocks antiviral IFN signaling. As the V proteins are important factors for host evasion, they represent logical targets for therapeutics directed against Henipavirus epidemics.

Antigens, Viral↗

PubMed2003

The p38 mitogen-activated protein kinase pathway and its role in interferon signaling.

Interferons (IFNs) are pleiotropic cytokines that exhibit multiple biological effects on cells and tissues. IFN receptors are expressed widely in mammalian cells and virtually all different cell types express them on their surface. The Type I IFN receptor has a multichain structure, composed of at least two distinct receptor subunits, IFNalphaR1 and IFNalphaR2. Two Jak-kinases, Tyk-2 and Jak-1, associate with the different receptor subunits and are activated in response to IFNalpha or IFNbeta to regulate engagement of multiple downstream signaling cascades. These include the Stat-pathway, whose function is essential for transcriptional activation of IFN-sensitive genes, and the insulin receptor substrate pathway, which regulates downstream activation of the phosphatidyl-inositol-3' kinase. Members of the Map family of kinases are also activated by the Type I IFN receptor and participate in the generation of IFN signals. The p38 Map kinase pathway appears to play a very important role in the induction of IFN responses. p38 is rapidly activated during engagement of the Type I IFN receptor, and such an activation is regulated by the small G-protein Rac1, which functions as its upstream effector in a tyrosine kinase-dependent manner. The activated form of p38 regulates downstream activation of other serine kinases, notably MapKapK-2 and MapKapK-3, indicating the existence of Type I IFN-dependent signaling cascades activated downstream of p38. Extensive studies have shown that p38 plays a critical role in Type I IFN-dependent transcriptional regulation, without modifying activation of the Stat-pathway. It is now well established that the function of p38 is essential for gene transcription via ISRE or GAS elements, but has no effects on the phosphorylation of Stat-proteins, the formation of Stat-complexes, and their binding to the promoters of IFN-sensitive genes. As Type I IFNs regulate gene expression for proteins with antiviral properties, it is not surprising that pharmacological inhibition of the p38 pathway blocks induction of IFNalpha-antiviral responses. In addition, pharmacological inhibition of p38 abrogates the suppressive effects of Type I IFNs on normal human hematopoietic progenitors, indicating a critical role for this signaling cascade in the induction of the regulatory effects of Type I IFNs on hematopoiesis. p38 is also activated during IFNalpha-treatment of primary leukemia cells from patients with chronic myelogenous leukemia. Such activation is required for IFNalpha-dependent suppression of leukemic cell progenitor growth, indicating that this pathway plays a critical role in the induction of the antileukemic effects of IFNalpha.

Gene Expression Regulation↗

PubMed2004

Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling.

Interferon (IFN)-lambda 1, -lambda 2, and -lambda 3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R beta, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-lambda 1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-lambda 1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-lambda 1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.

Antiviral Agents↗

PubMed1997

Interacting pathways of interferon signaling.

Interferons (IFNs) are important modifiers of biologic response in vertebrate cells. After IFNs are induced, in response to viral or microbial infections, the IFNs bind to specific receptors on the surface of target cells and cause rapid activation of IFN-stimulated genes. These genes mediate the different biologic effects of the IFNs. The molecular characterization of IFN-induced gene activation led to the discovery of the Jak-Stat signal transduction pathway, which is now known to be shared by many other cytokines, growth factors, and hormones. Protein phosphorylation plays a key role in the Jak-Stat pathway, which consists of a cascade of specific protein-protein interactions that culminate in protein-DNA engagement and specific transcription. Although responses in the signaling pathways to various IFN-alpha species have not been examined in detail, it is likely that subtle differences in receptor interaction between the various IFN-alpha species, whether derived from natural or synthetic genes, may produce an unexpected array of biologic effects and clinical responses.

Animals↗

PubMed2005

The PI3' kinase pathway in interferon signaling.

Interferons (IFNs) are pleiotropic cytokines with important immunomodulatory, antitumor, antiviral, and growth inhibitory properties. Consistent with the multiplicity of their effects, the IFNs activate several cellular cascades after they bind to their receptors. Although the Jak-Stat pathway is the most studied pathway, it appears that additional signaling cascades play roles in IFN signaling. The phosphatidylinositol 3'-kinase (PI3'K) pathway has emerged as one of the critical players in IFN signal transduction and is the focus of this review. This pathway is activated distinctively from the Stat pathway but plays important roles in the regulation of IFN-dependent gene transcription and initiation of mRNA translation.

Animals↗

PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗

PubMed2004

Mechanisms of type-I interferon signal transduction.

Interferons regulate a number of biological functions including control of cell proliferation, generation of antiviral activities and immumodulation in human cells. Studies by several investigators have identified a number of cellular signaling cascades that are activated during engagement of interferon receptors. The activation of multiple signaling cascades by the interferon receptors appears to be critical for the generation of interferon-mediated biological functions and immune surveillance. The present review summarizes the existing knowledge on the multiple signaling cascades activated by Type I interferons. Recent developments in this research area are emphasized and the implications of these new discoveries on our understanding of interferon actions are discussed.

Cell Cycle Proteins↗

PubMed2004

In psoriasis lesional skin the type I interferon signaling pathway is activated, whereas interferon-alpha sensitivity is unaltered.

The epidermal phenotype as observed in psoriatic skin results from inflammation and abnormal proliferation and terminal differentiation of keratinocytes. Mice deficient for interferon regulatory factor-2, a repressor of interferon signaling, display psoriasis-like skin inflammation. The development of this phenotype is strictly dependent on type I interferon (interferon-alpha/beta) signaling. The aim of this study was to assess the involvement of interferon-alpha/beta in the pathogenesis of human psoriasis. In psoriatic skin, we measured an increased expression of components that play central and crucial roles in interferon-alpha/beta signal transduction. Culturing keratinocytes or healthy skin biopsies with recombinant interferon-alpha stimulated this signaling pathway; however, this did not induce the expression of markers that are generally used to define the psoriasis phenotype. Furthermore, skin from psoriasis patients responded identically to interferon-alpha stimulation, demonstrating that psoriatic skin does not have an aberrant sensitivity to type I interferon. We conclude that in psoriatic lesional skin the type I interferon signaling pathway is activated, despite an unaltered interferon-alpha sensitivity. Our data furthermore show that type I interferon, in contrast to interferon-gamma, does not act directly on keratinocytes to induce a psoriatic phenotype. Thus, if the observed activated type I interferon signaling is indeed functionally involved in the pathogenesis of psoriasis, its contribution might be indirect, putatively involving other cell types besides keratinocytes.

Adolescent↗

PubMed1999

[Interferon signaling pathways].

Interferons (IFNs) encode a large family of multifonctional secreted proteins that are involved in antiviral defense, the regulation of cell growth and modulation of the immune response. They are subdivided into two types that activate transduction pathways via different cell surface receptors. Binding of both IFN type I and II results in the differential activation of JAK (Janus kinases) that phosphorylate latent cytoplasmic transcription factors termed STATs (signal transducer and activator of transcription). Phosphorylated STATs translocate to the nucleus, bind specific DNA elements and direct transcription. Type I IFN induces the phosphorylation of STAT1 and STAT2 proteins by tyrosine phosphorylation involving the type I IFN receptor-associated tyrosine kinases TYK2 and JAK1. Following phosphorylation, STAT1 and STAT2 form the transcriptionally active IFN-stimulated gene factor 3 (ISGF3) by association with a protein of the IFN regulatory factor (IRF) family, p48. The specificity of the transcriptional activation by ISGF3 is mediated by specific elements termed IFN-stimulatory response element (ISRE) located in the promoter region of IFN-inducible genes. ISREs drive the expression of most IFN type I-regulated genes and a few IFN type II-regulated genes. Gene induction by type II IFN involves the phosphorylation of only STAT1 by JAK1 and Jak2 kinases. This phosphorylation generates a homodimer of STAT1 which is able to bind the IFNgamma-activated site (GAS) to activate transcription. This signaling is rapid and direct. Molecules involved in the IFN signaling pathways have been shown to be used by other polypeptide ligands in their own signal transduction pathways. Pathways other than JAK/STAT are also involved in IFN signaling, but their mechanisms are less clear. The best documented are the mitogen-activated protein kinase (MAPK) cascade, the components of the TCR (T cell receptor) signaling cascade and the Pi3 kinase pathway.

Enzyme Activation↗

PubMed1996

Interferon signal transduction.

The interferon signal transduction pathway initiates at a cell surface receptor and mediates the activation of target genes in the nucleus. The binding of interferon to a transmembrane receptor stimulates the activation of associated tyrosine kinases of the Janus kinase (JAK) family. Subsequently, latent cytoplasmic transcription factors are activated by tyrosine phosphorylation and function as signal transducers and activators of transcription (STATs). Advances in the field of interferon research have contributed to our understanding of signal transduction induced by many cytokines that also use JAK/STAT signaling pathways to activate early response genes. The specificity of signal activation by distinct cytokines that share these signaling components, and the molecular interaction of the signaling components with each other and their respective cytokine receptors represent major areas of research that are beginning to be elucidated. Signaling molecules other than the JAKs and STATs have also been found to be activated following interferon binding. In addition, the induction of type I interferon stimulated genes by double-stranded RNA in the absence of interferon provides another pathway of specific gene activation.

Animals↗

PubMed2004

Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction.

Interferon (IFN)-alpha and -beta are the main cytokines for innate immune responses against viral infections. To replicate efficiently in the hosts, viruses have evolved various countermeasures to the IFN response. The V protein of measles virus (MV) has been shown to block IFN-alpha/beta signalling. Here, the wild-type IC-B strain of MV was shown to grow comparably in the presence and absence of IFN-alpha, whereas replication of the Edmonston tag strain recovered from cloned DNA was strongly suppressed in its presence. The V protein of the IC-B strain, but not the Edmonston tag strain, blocked IFN-alpha signalling. The V protein of the Edmonston strain from the ATCC also inhibited IFN-alpha signalling. There were three amino acid differences between the V proteins of the Edmonston ATCC and tag strains, and substitutions of both residues at positions 110 and 272 were required for the Edmonston ATCC V protein to lose IFN-antagonist activity. The P protein of the IC-B strain, which shares the N-terminal 231 aa residues with the V protein, also inhibited IFN-alpha signalling. Indeed, fragments comprising only those 231 residues of the IC-B and Edmonston ATCC V proteins, but not the Edmonston tag V protein, were able to block IFN-alpha signalling. However, the N-terminal region of the Edmonston tag V protein, when attached to the C-terminal region of the Edmonston ATCC V protein, inhibited IFN-alpha signalling. Taken together, our results indicate that both the N- and C-terminal regions contribute to the IFN-antagonist activity of the MV V protein.

Animals↗

PubMed2005

The p38 mitogen-activated protein kinase pathway in interferon signal transduction.

Interferons (IFNs) are cytokines that regulate a variety of biologic effects, including cellular antiviral responses, inhibition of proliferation, induction of differentiation, and immunoregulation, via different mechanisms. In order to mediate such pleiotropic effects, IFNs trigger numerous signaling events. One way for IFNs to regulate cellular functions is through activation of mitogen-activated protein (MAP) kinases. Three major cascades of MAP kinases are known. The c-Jun NH(2)-terminal kinase (JNK) cascade, the extracellular signal-regulated kinase (ERK) cascade, and the p38 MAP kinase cascade. ERK and p38 MAP kinases are activated in response to type I IFNs and participate in the regulation of cellular responses. In this review we discuss recent findings on the role of the p38 MAP kinase pathway and its function in mediating IFN-dependent biologic effects. We further dissect and discuss the roles of upstream and downstream components of the p38 MAP kinase in the control of cellular responses triggered by IFNs.

Animals↗

PubMed2005

CCAAT/enhancer binding proteins and interferon signaling pathways.

Interferons (IFNs) regulate a number of host responses, including innate and adaptive immunity against viruses, microbes, and neoplastic cells. These responses are dependent on the expression of IFN-stimulated genes (ISGs). Given the diversities in these responses and their kinetics, it is conceivable that a number of different factors are required for controlling them. Here, we describe one such pathway wherein transcription factor CAAAT/enhancer binding protein-beta (C/EBP-beta) is controlled via IFN-gamma-induced MAPK signaling pathways. At least two IFN-gamma-induced MAPK signals converge on to C/EBP-beta for inducing transcription. One of these, driven by extracellular signal-regulated kinases (ERKs), phosphorylates the C/EBP-beta protein in its regulatory domain. The second, driven by the mixed-lineage kinases (MLKs), induces a dephosphorylation leading to the recruitment of transcriptional coactivators.

Amino Acid Sequence↗

PubMed1996

Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the alpha and betaL subunits of the type I interferon receptor.

All Type I interferons (IFNalpha, IFNbeta, IFNomega) bind to the Type I IFN receptor (IFNR) and elicit a common set of signaling events, including activation of the Jak/Stat and IRS pathways. However, IFNbeta selectively induces the association of the alpha subunit of the Type I IFNR with p100, a tyrosyl phosphoprotein, to transduce IFNbeta-specific signals. Using antibodies raised against the different components of the Type I IFNR, we identified p100 as the long form of the beta subunit (betaL subunit) of the Type I IFNR. This was also confirmed in experiments with mouse L-929 cells transfected with truncated forms of betaL. Thus, IFNbeta stimulation of human cells or mouse L-929 transfectants expressing the human alpha and betaL subunits, selectively induces the formation of a signaling complex containing the alpha and betaL subunits of the receptor. The IFNbeta-regulated interaction of the alpha and betaL chains is rapid and transient and follows a similar time course with the tyrosine phosphorylation of these receptor components. These data demonstrate that the signaling specificity for different Type I IFNs is established early in the signaling cascade, at the receptor level, and results from distinct interactions between components of the Type I IFNR.

Animals↗

PubMed2006

Gamma interferon signaling: insights to development of interferon mimetics.

We have developed small peptide mimetics of gamma interferon (IFNgamma), based not on the classical model of IFNgamma initiated signaling by extracellular interaction, but rather on direct intracellular signaling by IFNgamma. IFNgamma, its receptor subunit IFNGR1, and transcription factor STAT1alpha are transported to the nucleus of cells as a complex where IFNgamma provides a classical polycationic nuclear localization sequence (NLS) for such transport. The C terminus of IFNgamma, represented here by the mouse IFNgamma peptide, IFNgamma(95-132), was capable of also forming a complex with IFNGR1 and STAT1alpha when introduced intracellularly and provided the NLS signaling for nuclear transport. Importantly, mouse IFNgamma(95-132) and human IFNgamma(95-134) mimetics both induced an antiviral state and upregulation of MHC class II molecules in cells similar to that of full length IFNgamma. Both IFNgamma and its peptide mimetics bind to an intracellular site, IFNGR1(253-287), on the cytoplasmic domain of receptor subunit IFNGR1. This binding plays a role in tyrosine phosphorylation events, catalyzed by JAK1 and JAK2 kinases that result in the phosphorylation and binding of STAT1alpha to the cytoplasmic domain of IFNGR1. Important structural requirements for IFNgamma mimetic activity are a polycationic NLS and an alpha helix in the mimetics. Finally, chromatin immunoprecipitations and reporter gene studies of IFNgamma and IFNgamma mimetic treated cells indicate that they, along with IFNGR1 and STAT1alpha, bind to the GAS element of IFNgamma activated genes and participate in STAT1alpha transcription. It is important to note that IFNgamma intracellular events played the key role in development of IFNgamma mimetics.

Active Transport, Cell Nucleus↗

PubMed2026

No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases.

Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.

Humans↗

PubMed2004

Herpes simplex virus 1 gene products occlude the interferon signaling pathway at multiple sites.

Earlier studies have shown that herpes simplex virus 1 (HSV-1) blocks the interferon response pathways, at least at two sites, by circumventing the effects of activation of protein kinase R by double-stranded RNA and interferon and through the degradation of promyelocytic leukemia protein (PML) since interferon has no antiviral effects in PML(-/-) cells. Here we report on two effects of viral genes on other sites of the interferon signaling pathway. (i) In infected cells, Jak1 kinase associated with interferon receptors and Stat2 associated with the interferon signaling pathway rapidly disappear from infected cells. The level of interferon alpha receptor is also reduced, albeit less drastically at times after 4 h postinfection. Other members of the Stat family of proteins were either decreased in amount or posttranslationally processed in a manner different from those of mock-infected cells. The decrease in the levels of Jak1 and Stat2 may account for the decrease in the formation of complexes consisting of Stat1 or ISGF3 and DNA sequences containing the interferon-stimulated response elements after exposure to interferon. (ii) The disappearance of Jak1 and Stat2 was related at least in part to the function of the virion host shutoff protein, the product of the viral U(L)41 gene. Consistent with this observation, a mutant lacking the U(L)41 gene and treated with interferon produced lesser amounts of a late protein (U(L)38) than the wild-type parent. We conclude that HSV-1 blocks the interferon signaling pathways at several sites.

Animals↗