Identification of the Zebrafish IFN Receptor: Implications for the Origin of the Vertebrate IFN System

Abstract

The recent description of virus-induced fish IFNs has raised questions about the evolution of this complex antiviral system. Identification of the receptor of the zebrafish virus-induced IFN (zIFN) was sought to help resolve these questions. We set up an experimental system to study the zIFN system in the course of a viral infection of zebrafish embryos. In this setting, zIFN was induced by viral infection, and we identified zIFN-dependent induced transcripts. Embryos quickly died from the infection, but zIFN overexpression increased their survival. We took advantage of this experimental system to perform in vivo loss and gain of function analysis of candidate receptors of the class II helical receptor family and identified zCRFB1 and zCRFB5 as the two subunits of the zebrafish IFN receptor. Based on the organization of the zIFN gene and the protein structure of the identified receptor components, the virus-induced fish IFNs appear as orthologs of mammalian IFN-λ, specifying type III IFN as the ancestral antiviral system of vertebrates.

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…Combined with the recent progress (Aggad et al, 2009;Biacchesi et al, 2009;Levraud et al, 2007;LopezMunoz et al, 2009), the present study suggests that there is a similar mechanism underlying IFN antiviral response in vertebrate species including fish. In this case, a further interest for future studies concerns about whether an ISGF3 complex is formed, translocated to the nucleus and then binds to the corresponding position of ISGs for initiation of their transcription.…”

“…These findings result in a debate for the nomenclature of fish IFN and also provoke a high interest in identifying their receptor complex. Notably, zebrafish virus-induced IFNs bind to distinct receptors that are not identical to mammals type I IFN receptors (Aggad et al, 2009;Levraud et al, 2007). These pronounced differences between fish and mammalian IFNs make it worthwhile to gain specific insights into fish IFN signaling pathway.…”

Fish viperin exerts a conserved antiviral function through RLR-triggered IFN signaling pathway

“…These fish IFNs can establish host antiviral state by inducing the expression of many fish IFN-stimulated genes (ISGs), such as PKR, Mx, ISG15 and some novel ISGs including PKZ, Gig1 and Gig2 (Langevin et al, 2013;Larsen et al, 2004;Li et al, 2012;Liu et al, 2011;Sun et al, 2014;Zhu et al, 2008). Fish viperin homologue is firstly identified in rainbow trout Oncorhynchus mykiss (Boudinot et al, 1999), and then in other fish species (Dang et al, 2010;Lee et al, 2013;Levraud et al, 2007;Padhi, 2013;Rise et al, 2008;Sun and Nie, 2004;Workenhe et al, 2009;Zhang et al, 2014;Zhang et al, 2007). Rainbow trout viperin is directly induced by VHSV without the requirement of ongoing protein synthesis and also by a rainbow trout IFN-like factor (Boudinot et al, 1999), indicating that there are IFN-dependent and IFN-independent pathways for rainbow trout viperin induction.…”

The Intracellular Signalling that Associated with Influenza A Virus Infection

“…IFN type II contains IFN-γ which is necessary for immune response to other pathogens more than viruses. IFN type III, which initiates signals through a receptor complex that have a role in antiviral response regulation [7]. Noteworthy, autophagy is originally described as the main catabolic pathway responsible for maintaining intracellular nutritional homeostasis that involves the formation of a unique vacuole, the autophagosome and the interaction with the endosomelysosome pathways [8,9,10].…”