Figure 3.

JAK-STAT signaling in response to mosquito-borne flavivirus infection and its antagonism in humans (A) and mosquitoes (B). (A) Following their production and release from human cells, type I IFNs (IFN-α and -β) bind to their cognate IFN-α receptor subunits 1 or 2 (IFNAR1 and IFNAR2) [85]. IFNAR activation results in phosphorylation of JAK1 and tyrosine kinase 2 (Tyk2) and the subsequent activation and homo- or heterodimerization of STAT1 or STAT2 [86]. STAT proteins then associate with IRF9 forming the interferon-stimulated genes factor 3 (ISGF3) complex which is translocated to the nucleus, promoting the transcription of IFN-stimulated genes (ISGs) [87,88]. (B) The JAK-STAT pathway in mosquitoes is activated upon the binding of the unpaired ligand (Upd) to the transmembrane receptor Domeless (Dome), an ortholog of the mammalian type I cytokine receptor during development [10,89]. The JAK-STAT pathway is also activated by the binding of Vago, an insect cytokine-like factor, to an unknown receptor which may suggest that Vago acts in a manner similar to IFNs in human cells [90]. Notably, Vago is induced via the RNAi pathway dsRNA sensor Dicer-2, indicating a cross-talk between these pathways in mosquitoes [91]. The binding of Upd and Vago to their cognate receptors leads to the phosphorylation of Hop, a homolog of the mammalian kinase JAK [10], which then results in phosphorylation of mosquito STAT proteins, which show a high degree of similarity to mammalian STAT5 [92]. STAT proteins are then translocated to the nucleus and consequently induce the transcription of JAK-STAT-regulated genes [76]. However, virus-encoded antagonists of mosquito-borne flaviviruses (DENV in purple, ZIKV in green, WNV in light blue, JEV in orange, YFV in black) are able to block these pathways in humans and mosquitoes. See main text for details.