| Abstrakt: |
Janus kinases (JAKs) bind to class I and II cytokine receptors, activating signaling and regulating gene transcription through signal transducer and activator of transcription (STAT) proteins. Type I interferons (IFNs) require the JAK members TYK2 and JAK1, which bind to the receptor subunits IFNAR1 and IFNAR2, respectively. We investigated the role of JAKs in regulating IFNAR signaling activity. Synthetic IFNARs in which the extracellular domains of IFNAR1 and IFNAR2 are replaced with nanobodies had near-native type I IFN signaling, whereas the homomeric variant of IFNAR2 initiated much weaker signaling, despite harboring docking sites for JAKs and STATs. Cells with JAK1 and TYK2 knockout (KO) showed residual signaling, suggesting partial complementation by the remaining JAKs, particularly when they were overexpressed. Live-cell micropatterning experiments confirmed the promiscuous binding of JAK1, JAK2, and TYK2 to IFNAR1 and IFNAR2, and their recruitment correlated with their relative cellular abundances. However, each JAK had a different efficacy in inducing cross-phosphorylation and downstream signaling. JAK binding was also promiscuous for other cytokine receptors, including IFN-L1, IL-10Rβ, TPOR, and GHR, but not for EPOR, which activated different downstream signaling pathways. These findings suggest that competitive binding of JAKs to cytokine receptors together with the varying absolute and relative abundances of the JAKs in different cell types can account for the cell type–dependent signaling pleiotropy of cytokine receptors. Editor's summary: Type I interferons (IFNs) stimulate antiviral or antiproliferative signaling in a cell type–dependent manner. The Janus kinases TYK2 and JAK1 are recruited to the IFN receptor subunits IFNAR1 and IFNAR2, respectively, cross-phosphorylating each other and STAT proteins to transduce IFN signals. However, in experiments with synthetic IFNARs and JAK-deficient cell lines, Zoler et al. found that multiple JAKs bound competitively to IFNARs to mediate signaling depending on their relative abundances. Other type I and II cytokine receptors exhibited promiscuous JAK recruitment, suggesting that competition among JAKs should be considered when developing JAK inhibitors as therapies to modulate cytokine signaling. —John F. Foley [ABSTRACT FROM AUTHOR] |
