Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates.

Nature 2014 10 10;514(7522):372-375. Epub 2014 Aug 10.

Immunobiology Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-α and β; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201573PMC
October 2014
41 Reads

Publication Analysis

Top Keywords

gene encoded
8
rnas bearing
8
bearing 5'-diphosphates
8
rig-i
7
mediates antiviral
4
l-a virus
4
antiviral responses
4
responses rnas
4
rig-i mediates
4
region 5'-end
4
virus base-paired
4
5'-end reviewed
4
reviewed rig-i
4
5'-diphosphates 5'pp
4
5'pp genomes
4
termini 5'pp-rna
4
5'pp-rna isolated
4
isolated yeast
4
5'pp termini
4
reoviruses 5'pp
4

References

(Supplied by CrossRef)

D Goubau et al.
Immunity 2013

M Schlee et al.
Immunobiology 2013

J Rehwinkel et al.
Curr. Opin. Microbiol. 2013

GH Holm et al.
J. Biol. Chem. 2007

H Kato et al.
J. Exp. Med. 2008

Y-M Loo et al.
J. Virol. 2008

A Pichlmair et al.
J. Virol. 2009

C Lu et al.
Structure 2010

D Luo et al.
Cell 2011

F Jiang et al.
Nature 2011

Y Wang et al.
Nature Struct. Mol. Biol. 2010

Similar Publications