Sensing of viral nucleic acids by RIG-I: From translocation to translation

Division of Clinical Pharmacology, Ludwig-Maximilian University Munich, Munich, Germany.
European journal of cell biology (Impact Factor: 3.83). 04/2011; 91(1):78-85. DOI: 10.1016/j.ejcb.2011.01.015
Source: PubMed


The innate immune system is a first layer of defense against infection by pathogens. It responds to pathogens by activating host defense mechanisms via interferon and inflammatory cytokine expression. Pathogen associated molecular patterns (PAMPs) are sensed by specific pattern recognition receptors. Among those, the ATP dependent helicase related RIG-I like receptors RIG-I, MDA5 and LGP2 sense the presence of viral RNA in the cytoplasm of host cells. While the precise PAMPs and functions of MDA5 or LGP2 are still unclear, RIG-I senses predominantly viral RNA containing a 5'-triphosphate along with dsRNA regions. Here we review our current knowledge of how these PAMPs are sensed and integrated by RIG-I, and how RIG-I's innate immune function can be used in translational medical approaches.

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Available from: Karl-Peter Hopfner, Feb 21, 2014
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    • "e l s e v i e r . c o m / l o c a t e / a n t i v i r a l production of type-I IFN with both therapeutic and prophylactic purposes (Olive, 2012; Schmidt et al., 2012). In this context, RNA transcripts mimicking structural domains in the non-coding regions of the foot and mouth disease virus (FMDV) genome (NCR-RNAs) have been recently found to be potent inducers of innate immune signaling. "
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    ABSTRACT: In this work we have addressed the effect of synthetic, non-infectious, RNA transcripts, mimicking structural domains of the non-coding regions (NCRs) of the foot-and-mouth disease virus (FMDV) genome on the infection of mice with Rift Valley fever virus (RVFV). Groups of 5 mice were inoculated intraperitoneally (i.p.) with 200 μg of synthetic RNA resembling the 5́-terminal S region, the internal ribosome entry site (IRES) or the 3'-NCR of the FMDV genome. RNA inoculation was performed 24 hours before (-24h), 24 hours after (+24h) or simultaneously to the challenge with a lethal dose of RVFV. Administration of the IRES RNA afforded higher survival rates than administration of S or 3'NCR transcripts either at -24h or +24h after challenge. In contrast, when RNA inoculation and viral challenge were performed simultaneously, all mice survived in both IRES- and 3'NCR-inoculated groups, with an 80% survival in mice receiving the S RNA. Among survivors, a complete correlation between significant anti-RVFV circulating antibody titers and resistance to a second lethal challenge with the virus was observed, supporting a limited viral replication in the RNA-inoculated animals upon the first challenge. All three RNA transcripts were able to induce the production of systemic antiviral and pro-inflammatory cytokines. These data show that triggering of intracellular pathogen sensing pathways constitutes a promising approach towards development of novel RVF preventive or therapeutic strategies.
    Antiviral Research 06/2014; 109(1). DOI:10.1016/j.antiviral.2014.06.010 · 3.94 Impact Factor
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    • "These small ligands, which bear phosphate groups (1–3) at the 5 end and hydroxyl groups at the 2 and 3 positions, serve as co-factor which can specifically interact with and thereby allosterically activate, existing RNaseL molecules (Knight et al., 1980; Zhou et al., 1997, 2005; Sarkar et al., 1999). As part of a physiological control system these 2–5A oligomers are quite unstable in that they are highly susceptible to degradation by cellular 5 -phosphatases and PDE12 (2 -phosphodiesterase; Silverman et al., 1981; Johnston and Hearl, 1987; Kubota et al., 2004; Schmidt et al., 2012). Viral strategies to evade or overcome this host defense mechanism ranges from preventing IFN signaling which would hinder the induction of OAS expression or thwarting activation of expressed OAS proteins by either shielding the viral dsRNA from interacting with it or modulating the host pathway to synthesize inactive 2–5A derivatives (Cayley et al., 1984; Hersh et al., 1984; Rice et al., 1985; Maitra et al., 1994; Beattie et al., 1995; Rivas et al., 1998; Child et al., 2004; Min and Krug, 2006; Sanchez and Mohr, 2007; Sorgeloos et al., 2013). "
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    ABSTRACT: The mammalian genome has evolved to encode a battery of mechanisms, to mitigate a progression in the life cycle of an invasive viral pathogen. Although apparently disadvantaged by their dependence on the host biosynthetic processes, an immensely faster rate of evolution provides viruses with an edge in this conflict. In this review, I have discussed the potential anti-virus activity of inositol-requiring enzyme 1 (IRE1), a well characterized effector of the cellular homeostatic response to an overloading of the endoplasmic reticulum (ER) protein-folding capacity. IRE1, an ER-membrane-resident ribonuclease (RNase), upon activation catalyses regulated cleavage of select protein-coding and non-coding host RNAs, using an RNase domain which is homologous to that of the known anti-viral effector RNaseL. The latter operates as part of the Oligoadenylate synthetase OAS/RNaseL system of anti-viral defense mechanism. Protein-coding RNA substrates are differentially treated by the IRE1 RNase to either augment, through cytoplasmic splicing of an intron in the Xbp1 transcript, or suppress gene expression. This referred suppression of gene expression is mediated through degradative cleavage of a select cohort of cellular RNA transcripts, initiating the regulated IRE1-dependent decay (RIDD) pathway. The review first discusses the anti-viral mechanism of the OAS/RNaseL system and evasion tactics employed by different viruses. This is followed by a review of the RIDD pathway and its potential effect on the stability of viral RNAs. I conclude with a comparison of the enzymatic activity of the two RNases followed by deliberations on the physiological consequences of their activation.
    Frontiers in Microbiology 06/2014; 5:292. DOI:10.3389/fmicb.2014.00292 · 3.99 Impact Factor
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    • "From the sites under selection identified for MDA5, the differences between MYXV host proteins are located in the CARD1 domain. The CARDs function as an interaction domain with other CARD-containing proteins, being fundamental for downstream MDA5 signaling (Bruns and Horvath 2012; Schmidt et al. 2012). Therefore, as functional constraints are expected in this domain, the observed variability Fig. 2 RIG-I cladogram representing relationships among leporids and the remaining mammalian species. "
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    ABSTRACT: One of the most severe European rabbit (Oryctolagus cuniculus) pathogens is myxoma virus (MYXV), a rabbit-specific leporipoxvirus that causes the highly lethal disease myxomatosis. Other leporid genera, Sylvilagus and Lepus, encompass species with variable susceptibilities to MYXV, but these do not develop the lethal form of the disease. The protective role of the retinoic acid-inducible gene-I (RIG-I/DDX58) in sensing MYXV in nonpermissive human myeloid cells prompted the study of the RIG-I-like receptor (RLR) family evolution in the three leporid genera. This viral-sensor family also includes the melanoma differentiation-associated factor 5 (MDA5/IFIH1), and the laboratory of genetics and physiology 2 (LGP2/DHX58). Considering specifically the MYXV susceptible host (European rabbit) and one of the virus natural long-term hosts (Sylvilagus bachmani, brush rabbit), the amino acid differences of positively selected sites in RIG-I between the two species were located in the protein region responsible for viral RNA recognition and binding, the repressor domain. Such differences might play a determinant role in how MYXV is sensed. When looking for episodic selection on MDA5 and LGP2 of the eastern cottontail (Sylvilagus floridanus), we also uncovered evidence of selective pressures that might be exerted by a species-specific leporipoxvirus, the Shope fibroma virus. Finally, a putative alternative splicing case was identified in Oryctolagus and Lepus MDA5 isoforms, corresponding to the deletion of one specific exon. This study provided the first insights into the evolution of the leporid RLR gene family that helps illuminate the origins of the species-specific innate responses to pathogens and more specifically to MYXV.
    Immunogenetics 11/2013; 66(1). DOI:10.1007/s00251-013-0740-7 · 2.23 Impact Factor
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