RIG-I and dsRNA-Induced IFNβ Activation

Stéphane Hausmann,Dominique Garcin,Jean-Baptiste Marq,Daniel Kolakofsky,Caroline Tapparel,Patricia Bozza

doi:10.1371/journal.pone.0003965

Abstract

Except for viruses that initiate RNA synthesis with a protein primer (e.g., picornaviruses), most RNA viruses initiate RNA synthesis with an NTP, and at least some of their viral pppRNAs remain unblocked during the infection. Consistent with this, most viruses require RIG-I to mount an innate immune response, whereas picornaviruses require mda-5. We have examined a SeV infection whose ability to induce interferon depends on the generation of capped dsRNA (without free 5′ tri-phosphate ends), and found that this infection as well requires RIG-I and not mda-5. We also provide evidence that RIG-I interacts with poly-I/C in vivo, and that heteropolymeric dsRNA and poly-I/C interact directly with RIG-I in vitro, but in different ways; i.e., poly-I/C has the unique ability to stimulate the helicase ATPase of RIG-I variants which lack the C-terminal regulatory domain.

Highlights

Virus infection elicits potent cellular responses that contain virus spread before the adaptive immune system can intervene, and the production of type I interferons (IFNa/b) is central to this process [1,2]
The binding of 59 triphosphorylated RNA to the RD of RIG-I leads to its dimerization, which is thought to stimulate the helicase ATPase and release the CARDs for homotypic interaction with IPS-1 [9], the mitochondrial adaptor of both RIG-I and mda-5
For mononegaviruses whose genome and antigenome RNAs are tightly covered with N protein during their synthesis, small promoter-proximal ppp RNAs are made independent of assembly with N [15,20,21]

Summary

Introduction

Virus infection elicits potent cellular responses that contain virus spread before the adaptive immune system can intervene, and the production of type I interferons (IFNa/b) is central to this process [1,2]. The sensors involved in coupling recognition of virus infection with the induction of IFNa/b have recently been discovered. These sensors, or pattern recognition receptors (PRRs) that recognize pathogen associated molecular patterns (PAMPs), include RIG-I and mda-5, two cytoplasmic, RNA-binding DExD/ H box helicases Both proteins contain N-terminal CARD domains, followed by a DECH box helicase. IPS-1 activation leads to the recruitment of a series of kinases which in turn leads to the activation of IRF-3/7 and NF-kB and the expression of the early IFN genes, such as IFNb

Methods

Results

Conclusion