DefinitionThis section has been translated automatically.
STAT1 stands for "Signal transducer and activator of transcription 1". STAT1 is a transcription factor that is encoded in humans by the gene of the same name. STAT1 is a member of the STAT protein family. All STAT proteins are phosphorylated by receptor-associated kinases. This process leads to their activation, dimerization by formation of homo- or heterodimers and finally translocation into the nucleus. Here, STAT molecules act as transcription factors.
Classification: For STAT1, there are two possible transcripts (due to alternative splicing) encoding 2 isoforms of STAT1:
- STAT1α, the full-length version of the protein, is the main active isoform responsible for most of the known functions of STAT1.
- STAT1ß, the short-length version, which lacks part of the C-terminus of the protein. STAT1ß appears to negatively regulate STAT1 activation or mediate IFN-γ-dependent anti-tumor and anti-infection activities.
General informationThis section has been translated automatically.
STAT1 can be activated by the following ligands:
- Interferon alpha (IFNα)
- Interferon gamma (IFNγ)
- Epidermal Growth Factor (EGF)
- Platelet Derived Growth Factor (PDGF)
- Interleukin 6 (IL-6)
- Interleukin-27 (IL-27)
After ligand binding to corresponding receptors, signal transduction occurs via kinases with phosphorylation and activation of the Janus kinases TYK2 and JAK1 and furthermore of STAT1 and STAT2. STAT molecules form dimers and bind to ISGF3G/IRF-9. ISGF3G/IRF-9 is the complex of interferon stimulated gene factor 3 (ISGF3G) with interferon regulatory factor 9 (IRF-9). This allows STAT1 to enter the nucleus. STAT1 has a key role in many gene expressions responsible for cell survival, viability, or response to pathogens. STAT1 expression can be induced with diallyl disulfide, a compound in garlic.
Clinical pictureThis section has been translated automatically.
Mutations in the STAT1 molecule can begain of function (GOF) or loss of function(LOF). Both can cause different phenotypes and symptoms. Recurrent common infections are common in both GOF and LOF mutations.
Loss of function: In STAT1 loss of function (i.e. STAT1 deficiency), two main genetic impairments are observed (see also under STAT1 gene).
First, there may be an autosomal recessive partial or even complete deficiency of STAT1. This causes intracellular bacterial diseases or viral infections and impaired IFN a, b, g and IL27 response. In the partial form, high levels of IFNgamma may also be found in blood serum. When tested from whole blood, monocytes do not respond to BCG and IFNgamma doses with IL-12 production. In the fully recessive form, there is very little response to antiviral and antifungal drugs.
On the other hand, partial STAT1 deficiency may also be caused by an autosomal dominant mutation that phenotypically results in a decreased IFNgamma response, burdening patients with selective intracellular bacterial disease (MSMD).
The gain-of-function mutation was first discovered in patients with chronic mucocutaneous candidiasis (CMC). Patients with STAT1 gain-of-function mutation and CMC respond poorly or not at all to treatment with azole drugs such as fluconazole, itraconazole or posaconazole . In addition to frequent viral and bacterial infections, these patients also develop autoimmunities. Inhibitors of the JAK/STAT pathway such as ruxolitinib are currently being tested and are a potential treatment choice for these patients.
LiteratureThis section has been translated automatically.
- Mork N et al (2015) Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun 16: 552-566
- Uzel G et al (2013) Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immun 131: 1611-1623.
- Vargas-Hernandez A et al (2018) Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immun 141: 2142-2155
- Yamazaki Y et al. (2014) Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J Immun 193: 4880-4887