There is considerable overlap between these two pathways as many IFN stimulated genes (ISGs) contain both ISRE and GAS sequences 4, 5. Similarly, type II interferon signals through STAT1/STAT1 homodimers that recognize genes containing gamma-activated sequences (GAS) in their promoters 5. Type I interferons signal through STAT1/STAT2 heterodimers to activate genes that contain IFN-sensitive response elements (ISRE) in their promoters 4. Following the binding of interferon to host cell receptors, phosphorylation by Janus kinases recruits STATs via their SH2 domains resulting in their phosphorylation, dimerization, and nuclear transport 2 whereupon they show high-affinity DNA-binding 3. Interferons (IFN) exert their rapid responses in defense against microbial infection through the signal transducers and activators of transcription (STATs) 1. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers.
Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced.
#Flow free bridges solution Activator
Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes.