Signal transducer and activator of transcription 4 (STAT4) is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
belonging to the
STAT protein
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
family, composed of
STAT1
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.
Function
All STAT molecules are phosphorylated by receptor associ ...
,
STAT2,
STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
,
STAT5A
Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the ''STAT5A'' gene. ''STAT5A'' orthologs have been identified in several placentals for which complete genome data are available.
Structure
STAT5a s ...
,
STAT5B,
STAT6
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 com ...
.
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
Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoveries ...
(JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive
CD4+ T cells
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
and
IFN-γ
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 ...
production in response to
IL-12.
There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ )production downstream.
Structure
Human as well murine STAT4 genes lie next to
STAT1
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.
Function
All STAT molecules are phosphorylated by receptor associ ...
gene locus suggesting that the genes arose by
gene duplication
Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. ...
.
STAT protein
STAT, Stat. , or stat may refer to:
* Stat (system call), a Unix system call that returns file attributes of an inode
* ''Stat'' (TV series), an American sitcom that aired in 1991
* Stat (website), a health-oriented news website
* STAT protein, a ...
s have six functional
domains: 1.
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
interaction domain – crucial for dimerization of inactive STATs and nuclear translocation; 2.helical coiled coil domain – association with regulatory factors; 3. central
DNA-binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
– binding to the enhancer region of IFN-γ activated sequence (GAS) family genes; 4. linker domain – assisting during the DNA binding process; 5. Src homology 2
(SH2) domain – critical for specific binding to the cytokine receptor after tyrosine phosphorylation; 6.
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
transactivation domain
The transactivation domain or trans-activating domain (TAD) is a transcription factor scaffold domain which contains binding sites for other proteins such as transcription coregulators. These binding sites are frequently referred to as activation ...
– triggering the transcriptional process.
The length of the protein is 748 amino acids, and the molecular weight is 85 941
Dalton
Dalton may refer to:
Science
* Dalton (crater), a lunar crater
* Dalton (program), chemistry software
* Dalton (unit) (Da), the atomic mass unit
* John Dalton, chemist, physicist and meteorologist
Entertainment
* Dalton (Buffyverse), minor cha ...
.
Expression
Distribution of STAT4 is restricted to
myeloid cells
A myelocyte is a young cell of the granulocytic series, occurring normally in bone marrow (can be found in circulating blood when caused by certain diseases).
Structure
When stained with the usual dyes, the cytoplasm is distinctly basophilic ...
,
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
and
testis
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
.
In resting human
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s it is expressed at very low levels, but its production is amplified by
PHA stimulation.
Cytokines activating STAT4
IL-12
Pro-inflammatory cytokine
IL-12 is produced in heterodimer form by
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s and
antigen-presenting cell
An antigen-presenting cell (APC) or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using ...
s. Binding of IL-12 to IL-12R, which is composed of two different subunits (IL12Rβ1 and IL12Rβ2), leads to the interaction of IL12Rβ1 and IL12Rβ2 with JAK2 and TYK2, which is followed by phosphorylation of STAT4 tyrosine 693. The pathway then induces
IFNγ
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 ...
production and Th1 differentiation. STAT4 is critical in promotion of antiviral response of
natural killer (NK) cell by targeting of promotor regions of Runx1 and Runx3.
IFNα and IFNβ
Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects. In viral infection signalling pathway, either of IFNα or β binds to IFN receptor (IFNAR), composed of IFNAR1 and IFNAR2, immediately followed by the phosphorylation of STAT1, STAT4 and IFN target genes. During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.
IL-23
Monocytes, activated dendritic cells (DC) and macrophages stimulate the accumulation of IL-23 after exposure to molecules of Gram-positive/negative bacteria or viruses. Receptor for IL-23 contains IL12β
1 and IL23R subunits, which upon binding of IL-23 promotes the phosphorylation STAT4. The presence of IL12β
1 enables similar, although weaker downstream activity as compared to IL-12. During chronic inflammation, IL-23/STAT4 signalling pathway is involved in the induction of differentiation and expansion of Th17 pro-inflammatory T helper cells.
Additionally, other cytokines like IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4.
Inhibitors of STAT4 signalling pathways
In cells with progressively increasing expression of IL12 and IL6, SOCSs production and activity suppress cytokine signalling and phosphorylation of JAK-STAT pathways in a negative feedback loop.
Other suppressors of the pathways are: protein inhibitor of activated STAT (PAIS) (regulation of transcriptional activity in the nucleus, observed in STAT4-DNA binding complex), protein tyrosine phosphatase (PTP) (removal of phosphate groups from phosphorylated tyrosine in JAK/STAT pathway proteins), STAT-interacting LIM protein (SLIM) (STAT ubiquitin E3 ligase blocking the phosphorylation of STAT4) or microRNA (miRNA) (degradation of STAT4 mRNA and its post-transcriptional regulation).
Target genes
STAT4 binds to hundreds of sites in the genome,
among others to the
promoters of genes for
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s (
IFN-γ
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 ...
,
TNF
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
), receptors (
IL18R1,
IL12rβ2,
IL18RAP), and signaling factors (
MYD88).
Disease
STAT4 is involved in several autoimmune and cancer diseases in animal models humans, significantly in the disease progression and pathology. STAT4 were significantly increased in patients with
colitis ulcerative and skin T cells of
psoriatic
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
patients. Moreover, STAT4 -/- mice developed less severe
experimental autoimmune encephalo-myelitis (EAE) than the wild type mice.
Intronic
single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNP) mostly in third intron of the STAT4 has shown to be associated with immune dysregulation and autoimmunity including
systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Comm ...
(SLE) and
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
as well as
Sjögren's disease (SD),
systemic sclerosis
Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are two ...
,
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
and also
type-1 diabetes. High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.
References
Further reading
*
External links
*
{{DEFAULTSORT:Stat4
Gene expression
Immune system
Proteins
Transcription factors
Signal transduction