The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a pathway with many functions, one of which is an anti-viral response. IFN-γ activates interferon gamma receptors 1 and 2 (INFGR1 and INFGR2), which are associated with Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) which leads to the phosphorylation of signal transducer and activator of transcription 1 (STAT1) homodimers. Phosphorylated STAT1 homodimers are translocated to the nucleus where it activates the transcription of gamma activated sequence (GAS) elements, which activates an inflammatory response and immunoregulation. INFGR1 and INFGR2 also phosphoylate STAT3 homodimers which are subsequently translocated to the nucleus where they also activate GAS elements. Type 1 interferons (IFNs) activate interferon alpha receptors 1 and 2 (IFNAR1 and IFNAR2) which are associated with tyrosine kinase 2 (TYK2) and JAK1 respectively. This receptor complex also phosphorylates STAT3 homodimers. The IFNAR complex phorphoylates STAT5 which binds with Crk-like protein (CRKL). This complex also activates the GAS elements in the nucleus. The main pathway of IFNAR1 and IFNAR2 is through the phosphorylation of STAT1 and STAT2. Together with interferon regulatory factor (IRF9) they form the interferon-stimulated gene factor 3 (ISGF3). The ISGF3 translocates to the nucleus and initiates the trascription of Interferon-sensitive response element (ISRE). This leads to an antiviral response, immunoregulation, antigen presentation, and checkpoint proteins. THE ISRE genes also activate IFN regulated genes. These along with lipopolysaccharides or foreign pathogens activates interferon Regulatory Factor 7 (IRF7). IRF7 is phosphorylated and bound with nuclear factor kappa B (NFKB). This causes the induction of type 1 INFs, which further activates the pathway. IFNAR1 and IFNAR2, activated by type 1 IFNs, signal through TYK2 and JAK1 to also trigger the activation of the NFKB pathway through phosphorylated STAT3, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs). They act through IKKa and IKKb to drive NFKB induction of genes associated with survival signals, antigen processing and presentation, and proliferation. Cytokines, like the various interleukins, activate their corresponding cytokine receptors/JAK complexes. This results in the phosphorylation of STATs, such as STAT3 and STAT5 or a STAT3 homodimer. These phosphorylated STATs are translocated to the nucleus where they transcribe genes involved in inflammation, angiogenesis, proliferation, and survival.

JAK/STAT Anti-viral Pathway References