Abstract
Viral infections are detected in most cases by the host innate immune system through pattern-recognition receptors (PRR), the sensors for pathogen-associated molecular patterns (PAMPs), which induce the production of cytokines, such as type I interferons (IFN). Recent identification in mammalian and teleost fish of cytoplasmic viral RNA sensors, RIG-I-like receptors (RLRs), and their mitochondrial adaptor: the mitochondrial antiviral signaling (MAVS) protein, also called IPS-1, highlight their important role in the induction of IFN at the early stage of a virus infection. More recently, an endoplasmic reticulum (ER) adaptor: the stimulator of interferon genes (STING) protein, also called MITA, ERIS and MPYS, has been shown to play a pivotal role in response to both non-self-cytosolic RNA and dsDNA. In this study, we cloned STING cDNAs from zebrafish and showed that it was an ortholog to mammalian STING. We demonstrated that overexpression of this ER protein in fish cells led to a constitutive induction of IFN and interferon-stimulated genes (ISGs). STING-overexpressing cells were almost fully protected against RNA virus infection with a strong inhibition of both DNA and RNA virus replication. In addition, we found that together with MAVS, STING was an important player in the RIG-I IFN-inducing pathway. This report provides the demonstration that teleost fish possess a functional RLR pathway in which MAVS and STING are downstream signaling molecules of RIG-I. The Sequences presented in this article have been submitted to GenBank under accession numbers: Zebrafish STING (HE856619); EPC STING (HE856620); EPC IRF3 (HE856621); EPC IFN promoter (HE856618).
Highlights
The innate immune system recognizes pathogen components through pattern-recognition receptors (PRRs) that are specific for conserved pathogen-associated molecular patterns (PAMPs), such as pathogen-derived nucleic acids and viral proteins
The stimulator of interferon genes (STING) protein from ZF4-7 cells is 99% identical to the sequence available in the bank with 3 amino acid differences: K113E, E205G and Q356R. This sequence was subjected to multiple alignments with the human, mouse, chicken and xenopus STING, showing that the sequence from zebrafish displays only a weak similarity with its counterparts (38–42%), except for certain motifs that are highly conserved among species, such as TM5 which was recently shown to be cytosolic and a dimerization domain [52]
Overexpression of STING Induces a Strong Antiviral State in Fish Cells against both RNA and DNA Viruses Since human and mouse STING overexpressions are sufficient to delay the replication of the vesicular stomatitis virus (VSV) [21], a RNA virus belonging to the Rhabdoviridae family, we examined whether the zebrafish STING could mediate a similar effect in fish cells
Summary
The innate immune system recognizes pathogen components through pattern-recognition receptors (PRRs) that are specific for conserved pathogen-associated molecular patterns (PAMPs), such as pathogen-derived nucleic acids and viral proteins. The recognition of PAMPs ligands leads to the activation of multiple signaling cascades that induce production of interferons (IFN) and other cytokines. This innate immune response is essential for successful pathogen early elimination and is crucial in the induction of the specific adaptive immune response. Among PRRs, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) play a key role in sensing non-self RNA in the cell cytosol and are essential in the early induction of type I IFN [1]. The ligand preferences of these proteins result in the detection of a wide variety of positive- and negativestranded RNA viruses, and indirectly some DNA viruses involving
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