Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency (original) (raw)
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Impaired response to interferon-α/β and lethal viral disease in human STAT1 deficiency
Nature Genetics, 2003
The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes 1 . STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria 2-5 . A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease 6 . No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease.
Impaired response to interferon-α/β and lethal viral disease in human STAT1 …
Nature genetics, 2003
The receptors for interferon-α/β (IFN-α/β) and IFN-γ activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes 1. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form γ-activated factor (GAF). ISGF3 is induced mainly by IFN-α/β, and GAF by IFN-γ, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-γ receptor (IFN-γR) are susceptible to infection with mycobacteria 2-5. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease 6. No individuals with deleterious mutations in the IFN-α/β signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-α/β nor IFN-γ activated STAT1-containing transcription factors. Like individuals with IFN-γR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-α/β in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-α/β thus results in susceptibility to viral disease.
A Novel STAT1 Mutation Associated with Disseminated Mycobacterial Disease
Journal of Clinical Immunology, 2012
STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961 T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GASluciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.
Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease
PLOS Genetics, 2006
The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.
Journal of Immunology, 1997
IFN signaling is mediated by binding of IFNs to their receptors and subsequent activation of Janus tyrosine kinase (JAK)-STAT signaling pathway. Stimulation of cells with IFN-a leads to the assembly of IFN-stimulated gene factor 3 transcription factor complex formed by STAT1 , STATZ, and p48 protein. IFN-y signaling is mediated by homodimeric STATl protein. Although these signaling molecules are expressed constitutively, there is also evidence of transcriptional regulation by IFNs. We have characterized the expression of STAT and IFN regulatory factor (IRF) family transcription factors in primary human blood mononuclear cells and macrophages in response to IFN-a and IFN-y stimulation. We show that IFN-a and IFN-y rapidly and efficiently enhanced STATI, STAT2, p48, and IRF-1 gene expression. IFN-y induced IRF-1 gene expression more strongly than IFN-a. Stimulation experiments in the presence of protein synthesis inhibitor, cycloheximide, suggested that these genes were activated directly by IFNs. IRF-2 gene was apparently only weakly responsive to IFNs in these cells. When macrophages were pretreated with low doses of IFN-y and then stimulated with IFN-a, clearly enhanced formation of specific transcription factor complexes was detected. This suggests that higher intracellular levels of STAT1, STATZ, and p48 protein may result in enhanced signal transduction for cytokines utilizing these transcription factors. C ytokine signal transduction from the cell surface receptor to the nucleus is mediated by receptor-associated Janus family tyrosine kinases (JAKs)' and STAT proteins (the JAK-STAT pathway). To date, four JAK kinase genes (JAKI, JAK2, JAK3, and TYK2) and seven STAT genes (STATI, 2, 3, 4, 5a, 5b, and 6) have been molecularly cloned. Receptor-associated ligand-activated JAKs phosphorylate STAT proteins on tyrosine residues, which leads to STAT protein activation, dimerization, translocation into the nucleus, and transcriptional activation of target genes. The IFN signaling system has functioned as a model for cytokine signaling in general (for reviews, see Refs. 1-3). IFNs are classified into type I (IFN-a,-p, and-m) and type I1 (IFN-y) IFNs and they have antiviral, antiproliferative, and immunomodulatory functions (4, 5). The two types of IFNs use distinct cell surface receptors, but their signal transduction pathways are partially overlapping. IFN-aP receptor-associated JAKl and TYK2 tyrosine phosphorylate STATl and STAT2 proteins. For full transcriptional activation, STATl also needs to be phosphorylated on a serine residue (6) by a serine-threonine kinase (mitogen-activated protein kinase) (7). Activated STATl and STAT2
EMBO reports, 2003
Stat1 (signal transducer and activator of transcription 1) regulates transcription in response to the type I interferons IFN-α and IFN-β, either in its dimerized form or as a subunit of the interferon-stimulated gene factor 3 (Isgf3) complex (consisting of Stat1, Stat2 and interferon-regulating factor 9). Full-length Stat1-α and the splice variant Stat1-β, which lacks the carboxyl terminus and the Ser727 phosphorylation site, are found in all cell types. IFN-induced phosphorylation of Stat1-α on Ser727 occurs in the absence of the candidate kinase, protein kinase C-δ. When expressed in Stat1-deficient cells, Stat1-β and a Stat1-S727A mutant both restored the formation of Stat1 dimers and of the Isgf3 complex on treatment with IFN-β. By contrast, only Stat1-α restored the ability of IFN-β to induce high levels of transcription from target genes of Stat1 dimers and Isgf3 and to induce an antiviral state. Our data suggest an important contribution of the Stat1 C terminus and its phosphorylation at Ser727 to the transcriptional activities of the Stat1 dimer and the Isgf3 complex.
2021
IFN-gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium, M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN-α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.
Blood, 2011
Subjects affected by Signal Transducer and Activator of Transcription 1 (STAT1) deficiency have lethal bacterial and viral infections. Complete STAT1 deficiency is inherited as an autosomal recessive disease; partial STAT1 deficiency is inherited as an autosomal recessive or autosomal dominant trait. Here, we report a patient who developed disseminated mycobacteriosis early in life and had several viral infections, including herpetic skin infection and interstitial pneumonia by cytomegalovirus with severe respiratory distress. Molecular analysis of STAT1 showed a novel homozygous mutation affecting a splice site, leading to exon 3 skipping and to synthesis of a lower molecular weight STAT1 protein. This mutation leads to marked reduction of STAT1 phosphorylation; the electromobility shift assay showed a complete defect of DNA-binding activity, which accounts for the complete impairment of peripheral blood mononuclear cell functional response to both IFN-γ and IFN-α. Moreover, analys...
Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils
Journal of leukocyte biology, 1999
Binding of interferon-gamma (IFN-gamma) to its heterodimeric receptor induces activation of the tyrosine kinases JAK1 and JAK2 followed by tyrosine phosphorylation of STAT1alpha. Selective activation of STAT1alpha at the IFN-gamma receptor is achieved by specific interaction between a cytosolic tyrosine motif including Y440 in the IFN-gamma receptor alpha-chain and the SH2 domain of STAT1alpha. We demonstrate that, in addition to STAT1alpha, STAT3 is also activated by IFN-gamma in human neutrophils. The activation of STAT3 was not found in human eosinophils, monocytes, and HL-60 cells, although the STAT3 protein was expressed in these cells. The cell type-specific activation of STAT3 by IFN-gamma was also observed in neutrophils that are differentiated in vitro from human CD34+ hematopoietic stem cells. These results indicate that a single cytokine receptor can activate different STAT family members in a cell-specific manner, which might result in cell-specific gene transcription.