Synthetic Heterodimers of Type III Interferon Receptors Require TYK2 for STAT Activation

Type III interferons (IFN-& lambda;) are central to host defense against viral infection of epithelial barrier surfaces. IFN-& lambda; binding to its receptor induces a JAK-STAT cascade through kinases Janus-associated kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), which are associated on either subunit of the heterodimeric type III IFN receptor. Recent studies have shown that TYK2 is not necessary for IFN-& lambda; to signal, in contrast to IFN-& alpha;, which uses the same JAK-STAT pathway activated by the type I IFN receptor. The mechanism for this differential TYK2 requirement is unknown. Our study uses synthetic IFN receptors in TYK2-deficient U2OS epithelial cells to define the processes in type I and III IFN signaling that require TYK2. We find that TYK2 deficiency reduces signaling equally from heterodimers of either type I or III IFN receptor intracellular domains. In contrast, JAK1-associated homodimers of IFNAR2 or IFNLR1 are both fully signaling competent even in the absence of TYK2. These results suggest that heterodimerization of the type III IFN receptor is insufficient to confer TYK2-independent signaling. Thus, we propose that noncanonical receptor complexes may participate in endogenous type III IFN signaling to confer TYK2-independent signaling downstream of IFN-& lambda; stimulation.

Automated summary

This study investigates the TYK2 dependency in type I and III interferon signaling using TYK2-deficient U2OS epithelial cells. The results show that TYK2 deficiency reduces signaling from both heterodimers of type I and III interferon receptors, while JAK1-associated homodimers are still fully competent in signaling independent of TYK2. The study suggests the involvement of noncanonical receptor complexes in TYK2-independent signaling downstream of type III interferon stimulation.