FIG. 2.

Proposed mechanisms of negative regulation of IFN responses by IFN-λ4. Binding of IFN-λ4 to its receptors IFNLR1 and IL10R2 leads to phosphorylation and dimerization of STAT1 and STAT2, recruitment of IRF9, and formation of ISGF3 complex. ISGF3 complex activates ISRE, leading to expression of multiple ISGs, including USP18 and ISG15. SOCS1 expression is also induced by IFN-λ4, although the role of the ISGF3 complex in SOCS1 induction is unclear. SOCS1 inhibits the formation of ISGF3 complex by inhibiting STAT1 phosphorylation by type III IFNs but to a lesser extent than by IFN-α. In contrast, USP18 inhibits binding of JAK1 to IFNAR2, thus reducing the effectiveness of IFN-α in activating the JAK/STAT pathway. USP18 also targets ISG15 for ubiquitination, thus inhibiting the process of ISGlyation. IL10R2, interleukin 10 receptor 2; ISGs, IFN-stimulated genes; ISRE, interferon-sensitive response element; SOCS1, suppressor of cytokine signaling. Color images are available online.