Unraveling the molecular mechanism governing the tissue specific expression of IFNλR1.

The functional receptor for type III interferons (IFNs) is a heterodimer of IFNLR1 and IL10R2. IFNLR1 is expressed in a highly tissue specific manner, with epithelial and liver tissue as the prime expressing tissues in humans. However, knowledge about the molecular pathways responsible for regulating the expression of IFNLR1 is yet unknown. In this study, various bioinformatics tools were used to predict the scores of signal peptides of IFNλR1 and IFNαR1, which was considered as an important difference in the expression of both receptors or participation in regulating the IFNLR1 gene. In silico study revealed that the signal peptide of IFNαR1 had more potential than the signal peptide of IFNλR1 but changing the signal peptide of wild type IFNλR1 with the signal peptide of IFNαR1 in wet lab had barely shown any differences. Selective expression of IFNλR1 was considered to be a plus point towards the targeted anti-viral activity of IFNλs but artificial control on its expression will surely make IFNλs a better drug with enhanced activity. The results of this study may help us in contributing some understanding towards the mechanisms involved in the selective expression of IFNLR1 and exceptionalities involved.

Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates.

Interferons (IFNs) play a major role in orchestrating the innate immune response toward viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been reported in a multitude of species, from bony fish to mammals. However, our current knowledge about the molecular function of fish IFNs as well as their evolutionary relationship to tetrapod IFNs is limited. Here we establish the three-dimensional (3D) structure of zebrafish IFNϕ1 and IFNϕ2 by crystallography. These high-resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs that play an immediate antiviral role: type I IFNs (e.g., alpha interferon [IFN-α] and beta interferon [IFN-ß]) and type III IFNs (lambda interferon [IFN-λ]), and each type is characterized by its specific receptor usage. Similarly, two groups of antiviral IFNs with distinct receptors exist in fish, including zebrafish. IFNϕ1 and IFNϕ2 represent group I and group II IFNs, respectively. Nevertheless, both structures reported here reveal a characteristic type I IFN architecture with a straight F helix, as opposed to the remaining class II cytokines, including IFN-λ, where helix F contains a characteristic bend. Phylogenetic trees derived from structure-guided multiple alignments confirmed that both groups of fish IFNs are evolutionarily closer to type I than to type III tetrapod IFNs. Thus, these fish IFNs belong to the type I IFN family. Our results also imply that a dual antiviral IFN system has arisen twice during vertebrate evolution.

The structure of human interferon lambda and what it has taught us.

Type III interferon (IFN) or IFN-lambda is a novel family of class II cytokines that induces antiviral activities both in vitro and in vivo through its own distinctive receptor complex. The recent crystal structure of human IFN-lambda3 revealed a cytokine with structural similarity to the interleukin-10 family, despite functionally being an IFN. Here, we review the structure of IFN-lambda and its relation to the other members of the class II cytokines. Further, we analyze the structural differences between the tree human isoforms of IFN-lambda and relate this to the observed differences in potency.

The two groups of zebrafish virus-induced interferons signal via distinct receptors with specific and shared chains.

Because the availability of fish genomic data, the number of reported sequences for fish type II helical cytokines is rapidly growing, featuring different IFNs including virus-induced IFNs (IFNphi) and IFN-gamma, and IL-10 with its related cytokines (IL-20, IL-22, and IL-26). Many candidate receptors exist for these cytokines and various authors have postulated which receptor chain would be involved in which functional receptor in fish. To date, only the receptor for zebrafish IFNphi1 has been identified functionally. Three genes encoding virus-induced IFNphis have been reported in zebrafish. In addition to these genes clustered on chromosome 3, we have identified a fourth IFNphi gene on chromosome 12. All these genes possess the intron-exon organization of mammalian lambda IFNs. In the zebrafish larva, all induce the expression of reporter antiviral genes; protection in a viral challenge assay was observed for IFNphi1 and IFNphi2. Using a combination of gain- and loss-of-function experiments, we also show that all zebrafish IFNphis do not bind to the same receptor. Two subgroups of fish virus-induced IFNs have been defined based on conserved cysteines, and we find that this subdivision correlates with receptor usage. Both receptor complexes include a common short chain receptor (CRFB5) and a specific long chain receptor (CRFB1 or CRFB2).