Crystal structure of zebrafish Interferons 1 and 2 reveals a conservation of type I Interferon structure in vertebrates

Interferons (IFNs) play a major role in orchestrating the innate immune response towards viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been described 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 3D structure of zebrafish IFN1 and IFN2 by crystallography. These high-resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs which play an immediate antiviral role: type I IFNs (e.g. IFN-α and IFN-β) and type III IFNs (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. IFN1 and IFN2 represent group I and group II, 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.