STAT1

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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C.

signal transducer and activator of transcription 1

CANDF7; IMD31A; IMD31B; IMD31C; ISGF-3; STAT91

Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF and other cytokines and other growth factors. Following type I IFN (IFN-alpha and IFN-beta) binding to cell surface receptors, signaling via protein kinases leads to activation of Jak kinases (TYK2 and JAK1) and to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize and associate with ISGF3G/IRF-9 to form a complex termed ISGF3 transcription factor, that enters the nucleus (PubMed:28753426).
ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of IFN-stimulated genes (ISG), which drive the cell in an antiviral state. In response to type II IFN (IFN-gamma), STAT1 is tyrosine- and serine-phosphorylated (PubMed:26479788).
It then forms a homodimer termed IFN-gamma-activated factor (GAF), migrates into the nucleus and binds to the IFN gamma activated sequence (GAS) to drive the expression of the target genes, inducing a cellular antiviral state. Becomes activated in response to KITLG/SCF and KIT signaling. May mediate cellular responses to activated FGFR1, FGFR2, FGFR3 and FGFR4.

Blood circulationISS:UniProtKB
Cellular response to insulin stimulusIEA:Ensembl
Cellular response to interferon-betaManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to interferon-gammaManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to organic cyclic compoundIEA:Ensembl
Cytokine-mediated signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Defense responseManual Assertion Based On ExperimentIBA:GO_Central
Defense response to virusManual Assertion Based On ExperimentIDA:UniProtKB
Interferon-gamma-mediated signaling pathwayManual Assertion Based On ExperimentIDA:BHF-UCL
Interleukin-27-mediated signaling pathwayManual Assertion Based On ExperimentIDA:ARUK-UCL
Macrophage derived foam cell differentiationManual Assertion Based On ExperimentIDA:UniProtKB
Metanephric mesenchymal cell differentiationISS:UniProtKB
Metanephric mesenchymal cell proliferation involved in metanephros developmentISS:UniProtKB
Negative regulation by virus of viral protein levels in host cellManual Assertion Based On ExperimentIMP:AgBase
Negative regulation of angiogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of endothelial cell proliferationManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesisISS:UniProtKB
Negative regulation of metanephric nephron tubule epithelial cell differentiationISS:UniProtKB
Negative regulation of transcription by RNA polymerase IIISS:UniProtKB
Positive regulation of defense response to virus by hostManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of erythrocyte differentiationManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of interferon-alpha productionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of mesenchymal cell proliferationISS:UniProtKB
Positive regulation of nitric-oxide synthase biosynthetic processIEA:Ensembl
Positive regulation of smooth muscle cell proliferationISS:UniProtKB
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Receptor signaling pathway via JAK-STATManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of apoptotic processManual Assertion Based On ExperimentTAS:UniProtKB
Regulation of cell population proliferationManual Assertion Based On ExperimentIBA:GO_Central
Renal tubule developmentManual Assertion Based On ExperimentIMP:UniProtKB
Response to cAMPISS:UniProtKB
Response to cytokineISS:UniProtKB
Response to hydrogen peroxideIEA:Ensembl
Response to interferon-betaManual Assertion Based On ExperimentIMP:UniProtKB
Response to mechanical stimulusIEA:Ensembl
Response to nutrientIEA:Ensembl
Response to peptide hormoneISS:UniProtKB
Response to xenobiotic stimulusIEA:Ensembl
Tumor necrosis factor-mediated signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Type I interferon signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB

Cytoplasm
Nucleus
Translocated into the nucleus upon tyrosine phosphorylation and dimerization, in response to IFN-gamma and signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4 (PubMed:15322115).
Monomethylation at Lys-525 is required for phosphorylation at Tyr-701 and translocation into the nucleus (PubMed:28753426).
Translocates into the nucleus in response to interferon-beta stimulation (PubMed:26479788).

Immunodeficiency 31B (IMD31B):
A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness.
Immunodeficiency 31A (IMD31A):
A form of Mendelian susceptibility to mycobacterial disease, a rare condition caused by impairment of interferon-gamma mediated immunity. It is characterized by predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine, environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. Clinical outcome severity depends on the degree of impairment of interferon-gamma mediated immunity. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. IMD31A has low penetrance, and affected individuals have relatively mild disease and good prognosis. IMD31A confers a predisposition to mycobacterial infections only, with no increased susceptibility to viral infections.
Immunodeficiency 31C (IMD31C):
A primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans.

Phosphorylated on tyrosine and serine residues in response to a variety of cytokines/growth hormones including IFN-alpha, IFN-gamma, PDGF and EGF. Activated KIT promotes phosphorylation on tyrosine residues and subsequent translocation to the nucleus. Upon EGF stimulation, phosphorylation on Tyr-701 (lacking in beta form) by JAK1, JAK2 or TYK2 promotes dimerization and subsequent translocation to the nucleus. Growth hormone (GH) activates STAT1 signaling only via JAK2. Tyrosine phosphorylated in response to constitutively activated FGFR1, FGFR2, FGFR3 and FGFR4. Phosphorylation on Ser-727 by several kinases including MAPK14, ERK1/2 and CAMKII on IFN-gamma stimulation, regulates STAT1 transcriptional activity. Phosphorylation on Ser-727 promotes sumoylation though increasing interaction with PIAS. Phosphorylation on Ser-727 by PRKCD induces apoptosis in response to DNA-damaging agents. Phosphorylated on tyrosine residues when PTK2/FAK1 is activated; most likely this is catalyzed by a SRC family kinase. Dephosphorylation on tyrosine residues by PTPN2 negatively regulates interferon-mediated signaling. Upon viral infection or IFN induction, phosphorylation on Ser-708 occurs much later than phosphorylation on Tyr-701 and is required for the binding of ISGF3 on the ISREs of a subset of IFN-stimulated genes IKBKE-dependent. Phosphorylation at Tyr-701 and Ser-708 are mutually exclusive, phosphorylation at Ser-708 requires previous dephosphorylation of Tyr-701.
Sumoylated with SUMO1, SUMO2 and SUMO3. Sumoylation is enhanced by IFN-gamma-induced phosphorylation on Ser-727, and by interaction with PIAS proteins. Enhances the transactivation activity.
ISGylated.
Mono-ADP-ribosylated at Glu-657 and Glu-705 by PARP14; ADP-ribosylation prevents phosphorylation at Tyr-701 (PubMed:27796300).
However, the role of ADP-ribosylation in the prevention of phosphorylation has been called into question and the lack of phosphorylation may be due to sumoylation of Lys-703 (PubMed:29858569).
Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense.
(Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22.