Alt. symbols: STAT91 | ISGF-3

Approved name: signal transducer and activator of transcription 1
Alt. names: signal transducer and activator of transcription 1, 91kD, signal transducer and activator of transcription 1, 91kDa | transcription factor ISGF-3 components p91/p84

Location: 2q32.2: 190908460 - 191020960 (-)
Gene type: protein_coding, 41 transcripts.

Scores: LoFtool: 0.151000 | pLI: 0.99999428 | LOEUF: 0.187

HGNC: 11362

NCBI: 6772, RefSeq: NG_008294.1

Ensembl: ENSG00000115415.21

LRG_111 | Status: public

OMIM: 600555

Expression | ProteinAtlas

STAT1 encodes a key transcription factor that mediates cellular responses to many key signaling molecules such as interferons (IFNs), cytokines (i.e. IL-17) and growth factors (i.e. KITLG/SCF, FGFs). STAT1 plays positive regulatory roles in the IFN-alpha/beta pathway, important for viral defense, and the IFN-gamma pathway, also relevant for mycobacterial defense. However, its activation is also important for modulating IL-17 pathway signaling, which is key in the response to Candidal infection. IFN cytokines binding to cell surface receptors leads to intracellular activation of the Jak kinases (TYK2 and JAK1) and downstream phosphorylation and dimerization of STAT1 with STAT2, but also with STAT3. The STAT dimers form different transcriptional complexes (i.e. ISGF3 in response to IFN-alpha/beta, GAF in response to IFN-gamma) that bind to IFN-responsive target genes in the nucleus, thereby inducing an anti-pathogen state in the cell (PMID: 28753426, 26479788).

STAT1 dysfunction is associated with susceptibility to 3 different types of infectious disease: mycobacterial, viral, and fungal (chronic mucocutaneous candidiasis-CMC). Thus, STAT1 mutations can lead to 3 kinds of primary immunodeficiency: 1) Immunodeficiency 31A, mycobacteriosis, autosomal dominant [MIM:614892]; 2) Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive [MIM:613796]; and 3) Immunodeficiency 31C, autosomal dominant [MIM:614162]. In general, patients with S TAT1 mutations causing mycobacterial and/or viral disease do not suffer from CMC (as the primary pathogenic mechanism involves dysregulated IFN signaling), and patients with CMC caused by other STAT1 mutations do not show increased risk for mycobacterial or viral diseases (as the primary pathogenic mechanism involves dysregulated IL-17 signaling). Loss-of-function (LOF) missense or frameshift mutations confer autosomal dominant or autosomal recessive susceptibility to intracellular agents through impairment of IFN?/IFN? immunity (viral diseases) and/or IFN? immunity (mycobacterial diseases). Patients with autosomal-dominant STAT1 deficiency show heterozygous mutations in the DNA-binding domain, the SH2 domain or the tyrosine residue Y701, which is mainly responsible for the activation of the protein through phosphorylation. Biallelic LOF mutations usually result in partial (or complete) deficiency of STAT1 protein and marked (or absolute) reduction of STAT1 phosphorylation and DNA-binding activity, predisposing patients to both viral and mycobacterial disease. Monoallelic dominant-negative LOF mutations in STAT1 usually result in partial STAT1 deficiency, predisposing to Mendelian susceptibility to mycobacterial disease. In contrast, monoallelic missense gain-of-function (GOF) mutations lead to autosomal dominant susceptibility to recurrent and severe fungal infections, mainly CMC, as a result of enhanced STAT1-mediated cellular responses to STAT1-dependent repressors and STAT3-dependent inducers of IL17-producing T cells. Some patients with GOF mutations can also show increased susceptibility to other infections and increased risk for autoimmunity or other forms of immune dysregulation (PMID: 27114460, 22651901). GOF mutations unfold their effect mainly by modulating the coiled-coil-domain, which in turn leads to an impairment of nuclear dephosphorylation of STAT1. Therefore, STAT1 remains activated at its DNA-binding site for a longer period, inhibiting genes necessary for TH17 development, relevant for the response against Candida albicans. [Load More]