The IFN-λ4 Conundrum: When a Good Interferon Goes Bad

Abstract

Since its discovery in 2013, interferon lambda 4 (IFN-λ4) has received a reputation as a paradoxical type III IFN. Difficulties in detecting IFN-λ4, especially in secreted form even led to questions about its existence. However, the genetic ability to generate IFN-λ4, determined by the presence of the rs368234815-ΔG allele, is the strongest predictor of impaired clearance of hepatitis C virus (HCV) infection in humans. Significant modulation of IFN-λ4 activity by a genetic variant (P70S) supports IFN-λ4, and not other type III IFNs encoded in the same genomic locus, as the primary functional cause of the association with HCV clearance. Although the ability to produce IFN-λ4 is associated with decreased HCV clearance, the recombinant IFN-λ4 is active against HCV and other viruses. These observations present an apparent conundrum-when and how does a presumably good IFN, with anti-HCV activity, interfere with the ability to clear HCV? In this review, we discuss findings that suggest potential mechanisms for explaining this conundrum.

Keywords: HCV; IFN-λ4; SOCS1; USP18; regulation; type III interferon.

FIG. 1.

IFN-λ4 as a member of the class-2 cytokine family. Protein sequences were downloaded from the UniProt Knowledgebase and structures from the RSCB Protein Data Bank. Computational tools were used to predict structure of IFN-λ4, for which crystal structure is not yet available. Multiple sequence alignments were generated, and phylogenetic reconstruction was carried out using the Markov Chain Monte Carlo Bayesian evolutionary analysis by sampling trees (MCMC BEAST, v1.7.4). The phylogenetic tree was graphed with FigTree v1.3.1. Clustering is based on protein sequence similarity, with the length of connecting lines representing the relative evolutionary distance from a common ancestral gene. IFN-λ4, interferon lambda 4.

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.