STAT1

STAT1, or Signal Transducer and Activator of Transcription 1, is a transcription factor that mediates cellular responses to cytokines and growth factors, most prominently the interferons. The STAT1 gene is located on chromosome 2q32.2 in humans. STAT1 functions as part of the JAK-STAT signaling pathway, transmitting signals from cytokine receptors to the nucleus to regulate gene expression.

Activation occurs when cytokine receptors engage ligands such as IFN-γ or type I interferons, leading to activation of associated JAK kinases (for example JAK1, JAK2, TYK2) that phosphorylate STAT1 on tyrosine 701. Phosphorylated STAT1 forms homodimers or heterodimers and translocates to the nucleus, where it binds gamma-activated sites (GAS) to drive transcription. Phospho-Ser727 enhances maximal transcriptional activity. In type I interferon signaling, STAT1 can also participate in the ISGF3 complex with STAT2 and IRF9, which binds ISREs to stimulate a broader set of interferon-stimulated genes.

STAT1 exists mainly as two isoforms, STAT1α and STAT1β. STAT1α is full-length and contains the transactivation domain; STAT1β lacks part of the C-terminal transactivation domain and has distinct regulatory properties. The ISGF3 complex that forms in type I IFN signaling includes STAT2 and IRF9 and expands the transcriptional response beyond GAS elements.

STAT1 activity is tightly regulated by phosphatases and negative regulators including SOCS proteins and PIAS1. Dysregulation of STAT1 can cause disease: loss-of-function mutations increase susceptibility to viral infections, while gain-of-function mutations can lead to chronic mucocutaneous candidiasis and autoimmunity due to excessive interferon signaling.