SOCS1 is an inducible negative regulator of IFN lambda induced gene expression in vivo

Abstract Type I (α and β) and type III (λ) interferons (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 signalling through the JAK-Stat pathway leading to the transcriptional induction of hundreds of IFN stimulated genes (ISGs), amongst them sensory pathway components such as cGAS, STING, RIG-I, MDA5 and the transcription factor IRF7 that enhance the induction of IFNαs and IFNλss. This positive feedback loop enables a very rapid and strong host response, which at some point has to be controlled by negative regulators to maintain tissue homeostasis. Type I IFN signalling is controlled by the inducible negative regulators suppressor of cytokine signalling 1 (SOCS1), SOCS3 and ubiquitin-specific peptidase 18 (USP18). The physiological role of these proteins in IFNλ signalling has not been clarified. Here we used knockout cell lines and mice to show that IFNλ signalling is regulated by SOCS1, but not by SOCS3 or USP18. These differences were the basis for distinct kinetic properties of type I and III IFNs. We found that IFNα signalling is transient and becomes refractory after hours, whereas IFNλ provides a long-lasting ISG induction.