Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. [5] [6] It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). [7] It functions as a transcription factor downstream of type I interferons. STAT2 sequence identity between mouse and human is only 68%. [8]
The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. In response to IFN, this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (IRF9) and form ISGF-3 (IFN-stimulated gene factor-3), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. [9] The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44. [10] ISGF-3 proceeds the activation of genes via the IFN-stimulated response element (ISRE). ISRE-driven genes include Ly-6C, the double-stranded RNA kinase (PKR), 2´ to 5´ oligoadenylate synthase (OAS), MX and potentially MHC class I. [11] Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with this protein, which is thought to be involved in the process of blocking IFN-alpha response by adenovirus. [6]
STAT2 knockout mice are unresponsive to type I IFN and extremely vulnerable to viral infection. They indicate the loss of the type I IFN autocrine loop and several defects in macrophages and T cell responses. Stat2-/- cells show differences in the biological response to IFN-α. [7]
STAT2 has been shown to interact with:
In double knockout STAT2 mice, an increased proliferation of M1, M2, and M1/M2 coexpressing macrophages during influenza-bacterial super-infection is observed. The bacterial clearance was also impaired by neutralization of IFN-γ (M1) and Arginase-1 (M2) what suggests that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Therefore the STAT2 signaling is associated with suppressing macrophage activation and bacterial control during influenza-bacterial super-infection. [24] These mice demonstrate no developmental defects. The knockout STAT2 and double knockout STAT mice in Vesicular stromatitis Indiana virus (VSV) model produce at least 10 times more virus plaque-forming units than the wild type (WT). [25] IFN-α pretreatment supplied protection in WT and STAT2+/- cells but not in double knockout STAT2 cells. IFN-γ pretreatment did not provide any antiviral response during infection of VSV. [26] This finding could be explained by the reduced level of STAT1 in cells of STAT2 knockout mice. [7] Additionally, the double knockout STAT2 mice are more sensitive to mouse cytomegalovirus (MCMV), severe fever thrombocytopenia syndrome virus, influenza virus, dengue virus (DNV) and Zika virus than control mice, which suggests that STAT2 plays a critical role in the suppression of virus replication in mice. [27] [28] [29] [30]
AR STAT2 deficiency was first time observed in 2 siblings. After routine immunization with measles-mump-rubella, one sibling developed disseminated vaccine-strain measles (MMR) but recovered and second sibling died in infancy from a viral infection due to primary immunodeficiency disorder. Later, the results showed that siblings were homozygous for absent expression of gene for STAT2. Patients with AR STAT2 deficiency have mutations which bring substitutions at important splice sites what leads to defected splicing and premature stop codons leading to a loss of expression of an interferon-stimulated gene. The typical clinical phenotype is disseminated infection after immunization with the live attenuated MMR vaccine. Some patients had also an onset of severe disease in infancy like infection with RSV, norovirus, coxsackievirus, adenovirus or enterovirus. One of the patients had CNS disease after the primary infection with EBV. EBV suppression was delayed in peripheral blood and cerebrospinal fluid as type I interferon signalling plays important role in the initial immune response against EBV. [31] During next 3 years, PCR test showed persistent EBV presence in blood as well as in cerebrospinal fluid despite anti-EBV IgG. CMV and VZV infections were severe as well in few patients. The virus infection was treated by high-dose of intravenous immunoglobulin (IVIG) after which patients recovered and became afebrile within 24 hours. IVIG has anti-inflammatory effect and suggests that the passive immunization could help to control the ongoing viral infections. Therefore, the monthly IgG therapy could be beneficial for patients with STAT2 deficiency during childhood, until their adaptive immune system has sufficiently developed. From the age 5 years, the frequency and severity of viral infections decreased and the age of 10 years the patients were mostly off all medication. In general, the patients with STAT2 deficiency are relatively healthy with no specific defects in their adaptive immunity or developmental abnormalities. These findings show that type I IFN signaling trough ISGF3 is not essential for host defense against the majority of common childhood viral pathogens. Despite a profoundly defective innate IFN response and evident susceptibility to some viral infections, STAT2-deficient individuals can live a relatively healthy life. [32]
It was also reported a homozygous STAT2 missense mutation (R148W/Q) which results to a STAT2 gain of function underlying fatal early-onset autoinflammation in three patients. This mutation leads to a persistent type I IFN response due to defective binding of the mutated STAT2 to ubiquitin specific peptidase 1 (USP18) which is an essential in the negative autofeedback loop where USP18 sterically hinders the binding of JAK1 to IFNAR1. [33] [34] Therefore complete AR STAT2 deficiency usually causes disseminated LAV infection and recurrent natural viral infections. Penetrance is not complete for several viral infections and for complicated live measles vaccine disease. [35] These observation suggest that the phenotype of AR STAT2 deficiency could range from asymptomatic (the healthy adult) to fatal (childhood death from a crushing viral disease). The phenotype is less severe than human complete AR STAT1 deficiency but more severe than IFNAR1 or IFNAR2 deficiency. The human phenotype is less severe than in mice.
Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.
Interferon tau is a Type I interferon made of a single chain of amino acids. IFN-τ was first discovered in ruminants as the signal for the maternal recognition of pregnancy and originally named ovine trophoblast protein-1 (oTP-1). It has many physiological functions in the mammalian uterus, and also has anti-inflammatory effect that aids in the protection of the semi-allogeneic conceptus trophectoderm from the maternal immune system.
Protein kinase RNA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene on chromosome 2. PKR is a serine/tyrosine kinase that is 551 amino acids long.
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.
Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.
Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellular protein modifier. The precise functions are diverse and vary among species but include potentiation of Interferon gamma (IFN-II) production in lymphocytes, ubiquitin-like conjugation to newly-synthesized proteins and negative regulation of the IFN-I response.
Interferon-alpha/beta receptor beta chain is a protein that in humans is encoded by the IFNAR2 gene.
Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors.
Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.
Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.
Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the IKBKE gene.
Interferon regulatory factor 9 is a protein that in humans is encoded by the IRF9 gene, previously known as ISGF3G.
Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene. The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular functions.
Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene. IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.
Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the USP18 gene. USP18 is induced by the immune response to type I and III interferons, and serves as a negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from a broad range of protein substrates, a process known as deISGylation.
Interferon-alpha/beta receptor alpha chain is a protein that in humans is encoded by the IFNAR1 gene.
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