UniProt functional annotation for P42224



	UniProt functional annotation for P42224

UniProt code: P42224.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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. {ECO:0000269|PubMed:12764129, ECO:0000269|PubMed:12855578, ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:8156998, ECO:0000269|PubMed:9724754}.

Subunit: Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation (PubMed:8605877, PubMed:28753426). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (PubMed:8605877). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (PubMed:9724754, PubMed:17897103). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr- 466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Found in a complex with NMI and CREBBP/CBP (PubMed:9989503). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (PubMed:9989503). Interacts with PTK2/FAK1 (PubMed:11278462). Interacts with SRC (By similarity). Interacts with ERBB4 (phosphorylated) (PubMed:18721752). Interacts with PARP9 and DTX3L independently of IFN- beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (PubMed:26479788). Interacts with OTOP1 (By similarity). Interacts with IFNGR1 (PubMed:8156998). {ECO:0000250|UniProtKB:P42225, ECO:0000269|PubMed:11278462, ECO:0000269|PubMed:17897103, ECO:0000269|PubMed:18721752, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:8156998, ECO:0000269|PubMed:8605877, ECO:0000269|PubMed:9121453, ECO:0000269|PubMed:9724754, ECO:0000269|PubMed:9989503}.

Subunit: (Microbial infection) Interacts with Sendai virus C', C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter.

Subunit: (Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter.

Subunit: (Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter. {ECO:0000269|PubMed:11442634, ECO:0000269|PubMed:15140960}.

Subunit: (Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation. {ECO:0000269|PubMed:15825084}.

Subunit: (Microbial infection) Interacts with ebolavirus protein VP24. {ECO:0000269|PubMed:22383882}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:27796300, ECO:0000269|PubMed:28753426}. Nucleus {ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426}. Note=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). {ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426}.

Ptm: 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. {ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:17897103, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:22065572, ECO:0000269|PubMed:26479788, ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:7543024, ECO:0000269|PubMed:7657660}.

Ptm: 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. {ECO:0000269|PubMed:15322115, ECO:0000269|PubMed:17897103, ECO:0000269|PubMed:21135090, ECO:0000269|PubMed:22065572, ECO:0000269|PubMed:7543024}.

Ptm: ISGylated. {ECO:0000269|PubMed:16139798}.

Ptm: 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). {ECO:0000269|PubMed:27796300, ECO:0000305|PubMed:29858569}.

Ptm: Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense. {ECO:0000269|PubMed:28753426}.

Ptm: (Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22. {ECO:0000269|PubMed:32699158}.

Disease: Immunodeficiency 31B (IMD31B) [MIM:613796]: A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness. {ECO:0000269|PubMed:12590259, ECO:0000269|PubMed:20841510, ECO:0000269|PubMed:23709754}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Immunodeficiency 31A (IMD31A) [MIM:614892]: 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. {ECO:0000269|PubMed:11452125, ECO:0000269|PubMed:16934001, ECO:0000269|PubMed:22573496}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Immunodeficiency 31C (IMD31C) [MIM:614162]: 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. {ECO:0000269|PubMed:21714643, ECO:0000269|PubMed:21727188, ECO:0000269|PubMed:23709754, ECO:0000269|PubMed:25288569, ECO:0000269|PubMed:26514428}. Note=The disease is caused by variants affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin- 17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643). {ECO:0000269|PubMed:21714643}.

Similarity: Belongs to the transcription factor STAT family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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. {ECO:0000269\|PubMed:12764129, ECO:0000269\|PubMed:12855578, ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:19088846, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:28753426, ECO:0000269\|PubMed:8156998, ECO:0000269\|PubMed:9724754}.


Subunit:		Isoform alpha homodimerizes upon IFN-gamma induced phosphorylation (PubMed:8605877, PubMed:28753426). Heterodimer with STAT2 upon IFN-alpha/beta induced phosphorylation (PubMed:8605877). The heterodimer STAT1:STAT2 forms the interferon-stimulated gene factor 3 complex (ISGF3) with IRF9 (By similarity). Interacts (phosphorylated at Ser-727) with PIAS1; the interaction results in release of STAT1 from its target gene (PubMed:9724754, PubMed:17897103). Interacts with IFNAR1; the interaction requires the phosphorylation of IFNAR1 at 'Tyr- 466' (PubMed:9121453). Interacts with IFNAR2 (PubMed:9121453). Found in a complex with NMI and CREBBP/CBP (PubMed:9989503). Interacts with NMI which is required for CREBBP/CBP recruitment to the complex (PubMed:9989503). Interacts with PTK2/FAK1 (PubMed:11278462). Interacts with SRC (By similarity). Interacts with ERBB4 (phosphorylated) (PubMed:18721752). Interacts with PARP9 and DTX3L independently of IFN- beta or IFN-gamma-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Interacts with histone acetyltransferase EP300/p300 in response to INF-gamma stimulation (PubMed:26479788). Interacts with OTOP1 (By similarity). Interacts with IFNGR1 (PubMed:8156998). {ECO:0000250\|UniProtKB:P42225, ECO:0000269\|PubMed:11278462, ECO:0000269\|PubMed:17897103, ECO:0000269\|PubMed:18721752, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:28753426, ECO:0000269\|PubMed:8156998, ECO:0000269\|PubMed:8605877, ECO:0000269\|PubMed:9121453, ECO:0000269\|PubMed:9724754, ECO:0000269\|PubMed:9989503}.
Subunit:		(Microbial infection) Interacts with Sendai virus C', C, Y1 and Y2 proteins, preventing activation of ISRE and GAS promoter.
Subunit:		(Microbial infection) Interacts with Nipah virus P, V and W proteins preventing activation of ISRE and GAS promoter.
Subunit:		(Microbial infection) Interacts with Rabies virus phosphoprotein preventing activation of ISRE and GAS promoter. {ECO:0000269\|PubMed:11442634, ECO:0000269\|PubMed:15140960}.
Subunit:		(Microbial infection) Interacts with HCV core protein; the interaction results in STAT1 degradation. {ECO:0000269\|PubMed:15825084}.
Subunit:		(Microbial infection) Interacts with ebolavirus protein VP24. {ECO:0000269\|PubMed:22383882}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:27796300, ECO:0000269\|PubMed:28753426}. Nucleus {ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:28753426}. Note=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). {ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:28753426}.
Ptm:		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. {ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:17561467, ECO:0000269\|PubMed:17897103, ECO:0000269\|PubMed:19088846, ECO:0000269\|PubMed:21135090, ECO:0000269\|PubMed:22065572, ECO:0000269\|PubMed:26479788, ECO:0000269\|PubMed:28753426, ECO:0000269\|PubMed:7543024, ECO:0000269\|PubMed:7657660}.
Ptm:		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. {ECO:0000269\|PubMed:15322115, ECO:0000269\|PubMed:17897103, ECO:0000269\|PubMed:21135090, ECO:0000269\|PubMed:22065572, ECO:0000269\|PubMed:7543024}.
Ptm:		ISGylated. {ECO:0000269\|PubMed:16139798}.
Ptm:		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). {ECO:0000269\|PubMed:27796300, ECO:0000305\|PubMed:29858569}.
Ptm:		Monomethylated at Lys-525 by SETD2; monomethylation is necessary for phosphorylation at Tyr-701, translocation into the nucleus and activation of the antiviral defense. {ECO:0000269\|PubMed:28753426}.
Ptm:		(Microbial infection) Ubiquitinated by Herpes simplex virus 2 E3 ubiquitin ligase ICP22. {ECO:0000269\|PubMed:32699158}.
Disease:		Immunodeficiency 31B (IMD31B) [MIM:613796]: A disorder characterized by susceptibility to severe mycobacterial and viral infections. Affected individuals can develop disseminated infections and die of viral illness. {ECO:0000269\|PubMed:12590259, ECO:0000269\|PubMed:20841510, ECO:0000269\|PubMed:23709754}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Immunodeficiency 31A (IMD31A) [MIM:614892]: 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. {ECO:0000269\|PubMed:11452125, ECO:0000269\|PubMed:16934001, ECO:0000269\|PubMed:22573496}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Immunodeficiency 31C (IMD31C) [MIM:614162]: 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. {ECO:0000269\|PubMed:21714643, ECO:0000269\|PubMed:21727188, ECO:0000269\|PubMed:23709754, ECO:0000269\|PubMed:25288569, ECO:0000269\|PubMed:26514428}. Note=The disease is caused by variants affecting the gene represented in this entry. STAT1 mutations in patients with autosomal dominant candidiasis lead to defective responses of type 1 and type 17 helper T-cells, characterized by reduced production of interferon-alpha, interleukin- 17, and interleukin-22. These cytokines are crucial for the antifungal defense of skin and mucosa (PubMed:21714643). {ECO:0000269\|PubMed:21714643}.
Similarity:		Belongs to the transcription factor STAT family. {ECO:0000305}.