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Review
. 2015 Apr:11:31-7.
doi: 10.1016/j.coviro.2015.01.012. Epub 2015 Feb 7.

Cytoplasmic sensing of viral nucleic acids

Matthias Habjan  1 , Andreas Pichlmair  2
Affiliations
Review

Cytoplasmic sensing of viral nucleic acids

Matthias Habjan et al. Curr Opin Virol. 2015 Apr.

Abstract

Viruses are the most abundant pathogens on earth. A fine-tuned framework of intervening pathways is in place in mammalian cells to orchestrate the cellular defence against these pathogens. Key for this system is sensor proteins that recognise specific features associated with nucleic acids of incoming viruses. Here we review the current knowledge on cytoplasmic sensors for viral nucleic acids. These sensors induce expression of cytokines, affect cellular functions required for virus replication and directly target viral nucleic acids through degradation or sequestration. Their ability to respond to a given nucleic acid is based on both the differential specificity of the individual proteins and the downstream signalling or adaptor proteins. The cooperation of these multiple proteins and pathways plays a key role in inducing successful immunity against virus infections.

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Figures

Figure 1
Figure 1
Viral nucleic acid sensor and effector proteins and their primary antiviral properties. Engagement of a particular set of nucleic acid sensors (Class I sensors, red) results in signal transduction events, leading to expression of the type I interferons IFN-α/β and other cytokines. These in turn upregulate additional sensors (Class II sensors, green) with the ability to modulate the cellular machinery. In addition cytokines induce expression of effector proteins (blue) directly targeting viral nucleic acids. Transmission of signals in some pathways occurs through second messengers (yellow). Class II sensors include PKR, OAS and AIM2. PKR phosphorylates translation initiation factor eIF2α and consequently inhibits translation. Activated OAS synthesises the second messenger 2′5′ oligoA, which then binds to and activates the latent endoribonuclease RNASEL. Activation of the inflammasome, a large multimeric complex including pro-caspase-1, is mediated by the DNA sensor AIM2. Caspase-1 cleaves its substrates pro-IL-1b and IL-18 for extracellular release. For signal transduction, MDA5 and RIG-I (either activated directly or through binding of RNAPIII-synthesised PPP-RNA) engage the adaptor protein MAVS. cGAS and IFI16 transmit their signal to the adaptor STING. Both pathways culminate in phosphorylation and dimerization of IRF-3 as well as release of active NFκB into the nucleus, where they cooperate to form an enhanceosome to turn on transcription of cytokine genes. Abbreviations: OAS, 2′5′ oligoadenylate synthetase; PKR, dsRNA-dependent protein kinase R; AIM2, absent in melanoma 2; eIF2α, eukaryotic initiation factor 2 alpha subunit; RNASEL, 2-5A-dependent ribonuclease L; MDA5, melanoma differentiation-associated protein 5; RIG-I, retinoic acid inducible gene I; RNAPIII, RNA polymerase III; cGAS, cyclic GMP–AMP synthase; IFI16, interferon gamma-inducible protein 16; MAVS, mitochondrial antiviral-signalling protein; STING, stimulator of interferon genes; IRF-3, interferon regulatory factor 3; NFκB, nuclear factor κ-light-chain enhancer of activated B cells; IFIT, interferon-induced protein with tetratricopeptide repeats; APOBEC3, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3; ADAR1, RNA-specific adenosine deaminase 1; TREX1, three prime repair exonuclease 1; PPP-RNA, 5′ triphosphorylated RNA.
Figure 2
Figure 2
Differences between cellular and viral nucleic acids. Synthesis of host RNA (red) from nuclear dsDNA (blue) is achieved by three cellular RNA polymerases. RNA polymerase II synthesises mRNA, ncRNA and some snRNAs, whereas RNA polymerase III generates tRNA and 5S rRNA. rRNAs are produced by RNA polymerase I. Virus-derived DNA and RNA are present in the cell either as genomes, transcripts or replication by-products. Indicated are particular differences at the RNA 5′ and 3′ end, such as cap structures and methylations (e.g. cellular mRNA harbouring an N7-methylated guanine cap structure and 2′O-methylation at the first and/or second ribose). *5S rRNA harbours a 5′ triphosphate group; **U6 and 7SK RNA both have a 5′ gamma-monomethyl phosphate, and SRP RNA has a 5′ triphosphate. Abbreviations: ds, double-stranded; mRNA, messenger RNA; rRNA, ribosomal RNA; tRNA, transfer RNA; snRNA, small nuclear RNA; ncRNA, non-coding RNA; m7G, N7-methylated guanine cap; m, 2′O-methylation; p, phosphate group; TMG, hypermethylated 2,2,7-trimethylguanosine cap; VPg, viral protein genome-linked; A(n), poly(A) tail.
Figure 3
Figure 3
Cellular proteins involved in sensing and engagement of viral nucleic acids. Antiviral nucleic acid sensors operate in three layers, including viral sensing leading to signal transduction (red), modulation of the cellular machinery (green), and direct targeting of viral nucleic acids (blue). The exact mechanisms of particular cellular proteins engaging specific viral RNA and DNA structures are described in detail in the text. Abbreviations: ss, single-stranded; ds, double-stranded; Cap0, m7G cap structure lacking 2′O-methylation at the first and/or second ribose; PPP-RNA, 5′ triphosphorylated RNA; PP-RNA, 5′ dephosphorylated RNA; cccDNA, covalently closed circular DNA.
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