Zebrafish ISG15 exerts a strong anti-viral activity against RNA and DNA viruses and regulates the interferon response
- Authors
- Langevin, C., van der Aa, L.M., Houel, A., Torhy, C., Briolat, V., Lunazzi, A., Harmache, A., Bremont, M., Levraud, J.P., and Boudinot, P.
- ID
- ZDB-PUB-130711-6
- Date
- 2013
- Source
- Journal of virology 87(18): 10025-36 (Journal)
- Registered Authors
- Briolat, Valerie, Levraud, Jean-Pierre
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Line
- DNA Viruses/immunology*
- Interferons/biosynthesis
- Interferons/immunology*
- Molecular Sequence Data
- Protein Binding
- Protein Processing, Post-Translational
- RNA Viruses/immunology*
- Sequence Analysis, DNA
- Ubiquitin/genetics
- Ubiquitin/immunology*
- Viral Proteins/metabolism*
- Zebrafish/genetics
- Zebrafish/immunology*
- Zebrafish/virology
- PubMed
- 23824820 Full text @ J. Virol.
ISG15, a 15kDa interferon-induced protein that participates in anti-viral defenses of mammals, is highly conserved among vertebrates. In fish, as in mammals, viral infection and interferon treatment induce isg15 expression. The two ubiquitin-like domains of ISG15 and the presence of a consensus LRLRGG sequence in the C-terminal region, which is required for the covalent conjugation to a substrate protein, are also conserved in fish. Our data demonstrate that over-expression of zebrafish ISG15 (zf-ISG15) in EPC cells is sufficient to inhibit viral infection by RNA viruses belonging to Novirhabdovirus and Birnavirus genus and by DNA viruses of the Iridovirus genus. In co-expression experiments with IHNV proteins, we demonstrate specific ISGylation of P and NV proteins. Mutation of the glycine residues in the consensus LRLRGG motif abolishes zf-ISG15 conjugation to these proteins and the cellular protection against viral infection, thus connecting ISGylation and ISG15-dependent viral restriction. Additionally, zf-ISG15 over-expression triggers induction of rig-I and viperin genes as well as ifn to a lesser extent. Overall, our data demonstrate the anti-viral effect of a fish ISG15 protein, revealing the conservation, among vertebrates, of an ISGylation mechanism likely directed against viruses. Furthermore, our findings indicate that zf-ISG15 affects the IFN system at several levels, and its study shall shed further light on the evolution of the complex regulation of the innate anti-viral response in vertebrate cells.