STAT4


Signal transducer and activator of transcription 4 is a transcription factor belonging to the STAT protein family. It is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12.

Structure

Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication. STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal transactivation domain. The length of the protein is 748 amino acids, and the molecular weight is 85 941 Dalton.

Expression

Distribution of STAT4 is restricted to myeloid cells, thymus and testis. In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.

Activation

Two chains of IL-12 receptor form heterodimer after IL-12 binding and activate the receptor associated JAK kinases, termed JAK2 and TYK2. Stat4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain and translocates into nucleus to activate gene transcription.

Target genes

STAT4 binds to hundreds of sites in the genome, among others to the promoters of genes for cytokines, receptors, and signaling factors.

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 patients. Moreover, STAT4 -/- mice developed less severe experimental autoimmune encephalo-myelitis than the wild type mice.
Intronic single nucleotide polymorphism mostly in third intron of the STAT4 has shown to be associated with immune dysregulation and autoimmunity including systemic lupus erythematosus and rheumatoid arthritis as well as Sjögren's disease, systemic sclerosis, psoriasis 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.