Fig 1. IFN activation of the JAK-STAT signaling pathway.

Free IFN binds to the IFNAR subunits 1 and 2 to form an active complex. After IFNAR activation the signal is transduced inside the cytoplasm; here STAT1 and STAT2 are phosphorylated. Phosphorylated forms of STAT1 and STAT2 form a heterodimer (dimerSTAT). dimerSTAT interacts with IRF9 to form ISGF3 (a trimolecular complex). ISGF3 translocates to the nucleus. In the nucleus, ISGF3 binds to free transcription factor binding sites (ISRE), inducing transcriptional activity leading to production of more IRF9 as a positive feedback and SOCS as a negative feedback given by the SOCS1 degradation of active receptors. ISGF3 induces the expression of around 350 different ISGs, including MxA and IFIT1. Additionally, there is a constitutive formation of STAT2-IRF9 heterodimers, that stimulate the expression of interferon-induced genes (ISGs) without a signaling requirement (basal expression). The model consists of 42 species in two compartments and 62 kinetic reactions and is fully described in the methods section. In the figure, boxes represent the chemical species, empty symbols represent degradation processes, arrows represent the reactions described in Section B.1 in S1 Text, initial conditions and parameters are given in Tables 1, 2 and 3, respectively. The pathway diagram was created with the Newt Editor [26, 27] following the Systems Biology Graphical Notation (SBGN) [28].