Transcriptional regulation by STAT6

Abstract

Signal transducer and activator of transcription (STAT) proteins are critical mediators of cytokine signaling. Among the seven STAT proteins, STAT6 is activated by IL-4 and IL-13 and plays a predominant role in the immune system. However, there is increasing evidence that STAT6 may function in other tissues and organ systems. IL-4, IL-13, and STAT6 promote humoral immunity, clearance of helminthic parasites as well as the pathogenesis of allergic disorders like asthma, food allergies, and atopic dermatitis. In this review, we will describe our current understanding of the biological functions of STAT6 and summarize recent advances in understanding the molecular mechanisms by which STAT6 regulates transcription.

Fig. 1

Schematic of STAT6. The STAT6 molecule contains a N-terminal coiled coil domain (CCD), a DNA-binding domain (DBD), a SH2 domain, a conserved tyrosine, and the C-terminal transactivation domain (TAD). The TAD has specific regions that associate with transcriptional coactivators CBP/p300 and NCoA-1

Fig. 2

Target genes of STAT6 in various cell types

Fig. 3

Model for STAT6-regulated transcription. Under non-stimulating conditions, PARP-14 is bound to STAT6-responsive promoters and recruits HDAC 2 and 3 and keeps the gene silent. Upon IL-4 stimulation, STAT6 is activated and binds to its promoter element and induces the PARP-14 enzymatic activity that modifies itself, p100, HDAC 2 and 3 in the complex. This results in the dissociation of PARP-14 and the HDACs from the promoter and allows for p300/CBP, NCoA-,1 and NCoA-3 to be recruited to the promoter for histone acetylation. The p100 complex with RNA helicase A forms a bridge between STAT6 and the RNA polymerase II complex. STAT6 collaborates with several other transcription factors to activate transcription