Abstract
Type I (α and β) and type III (λ) IFNs are induced upon viral infection through host sensory pathways that activate IFN regulatory factors (IRFs) and nuclear factor κB. Secreted IFNs induce autocrine and paracrine signaling through the JAK-STAT pathway, leading to the transcriptional induction of hundreds of IFN-stimulated genes, among them sensory pathway components such as cGAS, STING, RIG-I, MDA5, and the transcription factor IRF7, which enhance the induction of IFN-αs and IFN-λs. This positive feedback loop enables a very rapid and strong host response that, at some point, has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signaling is controlled by the inducible negative regulators suppressor of cytokine signaling 1 (SOCS1), SOCS3, and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFN-γ signaling has not been clarified. Here we used knockout cell lines and mice to show that IFN-λ signaling is regulated by SOCS1 but not by SOCS3 or USP18. These differences were the basis for the distinct kinetic properties of type I and III IFNs. We found that IFN-α signaling is transient and becomes refractory after hours, whereas IFN-λ provides a long-lasting IFN-stimulated gene induction.
Highlights
Type I and type III IFNs are induced in virus-infected cells and provide an important first line of defense through the rapid induction of hundreds of IFN-stimulated genes (ISGs)3 that collectively establish an antiviral state
Activation of the IFNLR by ligand binding results in the activation of interferon-stimulated gene factor 3 (ISGF3) and STAT1 homodimers, the same transcription factor complexes that are induced by type I IFNs
We investigated the role of suppressor of cytokine signaling 1 (SOCS1), SOCS3, and Ubiquitin-specific peptidase 18 (USP18) in IFN- signaling in cells with physiological IFNLR expression and deletion or overexpression of all three inhibitors and in mice deficient for SOCS1 or USP18
Summary
IFN- induces sustained gene expression in cells despite strong induction of USP18. The selective and restricted expression of IFNLR1 limits the biological activity range of IFN- primarily to mucosal epithelial tissues [27]. Mid was significantly enhanced at some time points in SOCS1 and SOCS3 knockout cells (Fig. 3 and supplemental Fig. 2) We confirmed these findings by quantifying the expression levels of ISGs, including RSAD2, GBP5, and IFI27, as well as the three inducible regulators, SOCS1, SOCS3, and USP18, in the knockout cell lines after stimulation with IFN-1 and IFN-␣ (Fig. 4 and supplemental Fig. 3). The effect of Usp knockout on IFN- signaling was minimal, with only Rsad and Ifi being significantly increased at one time point in the gut and lung, respectively (Fig. 6 and supplemental Fig. 4B) From these results, we conclude that IFN-␣ signaling in these mice is predominantly inhibited by Usp, whereas IFN- signaling is regulated by Socs.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
