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.
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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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    • "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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