Discrimination of Self and Non-Self Ribonucleic Acids

Abstract

Most virus infections are controlled through the innate and adaptive immune system. A surprisingly limited number of so-called pattern recognition receptors (PRRs) have the ability to sense a large variety of virus infections. The reason for the broad activity of PRRs lies in the ability to recognize viral nucleic acids. These nucleic acids lack signatures that are present in cytoplasmic cellular nucleic acids and thereby marking them as pathogen-derived. Accumulating evidence suggests that these signatures, which are predominantly sensed by a class of PRRs called retinoic acid-inducible gene I (RIG-I)-like receptors and other proteins, are not unique to viruses but rather resemble immature forms of cellular ribonucleic acids generated by cellular polymerases. RIG-I-like receptors, and other cellular antiviral proteins, may therefore have mainly evolved to sense nonprocessed nucleic acids typically generated by primitive organisms and pathogens. This capability has not only implications on induction of antiviral immunity but also on the function of cellular proteins to handle self-derived RNA with stimulatory potential.

Keywords: MDA5; PRR; RIG-I; antiviral mechanisms; interferon; ribonucleic acid sensing.

FIG. 1.

Viral nucleic acids trigger a variety of events that are governed by a variety of specific cellular sensor proteins. Despite that these sensor proteins can identify the same type of viral nucleic acid, the antiviral and cellular effects are diverse. A key function of viral nucleic acids is the induction of cytokines, which regulate expression of many antiviral proteins, including sensor or effector proteins with affinity for the same viral nucleic acids. Engagement of these proteins with viral nucleic acid leads to changes in biological activity of cellular functions or in direct viral inhibition.

FIG. 2.

Stimulatory and nonstimulatory RNAs in cells. This schematic provides an overview of the main proportion of cellular RNAs and cytoplasmic RIG-I and MDA5 stimulatory RNAs. Host RNAs are synthesized by RNA polymerase I–III (Pol-I, Pol-II, and Pol-III) in the nucleus. The RNAs are generated as a precursor RNA bearing a 5′ triphosphate group, which is extensively modified in the nucleus before getting transported to the cytoplasm where they perform their biological function. snRNAs are further modified in the cytoplasm and reimported to the nucleus. Nonstimulatory cytoplasmic cellular RNA (blue box) are not activating cytoplasmic PRRs. Specific viruses can introduce different types of stimulatory RNA during the infection process. These RNAs often resemble premature forms of cellular RNA and can be classified into RIG-I (green box) and MDA5 ligands (orange box). AAA, poly(A) tail; DI genomes, defective interfering genomes; dsRNA, double-stranded ribonucleic acid; MDA5, melanoma differentiation-associated protein 5; me, methyl group; mRNA, messenger RNA; P, phosphate group; PRR, pattern recognition receptor; RIG-I, retinoic acid-inducible gene I; rRNA, ribosomal RNA; snRNA, small nuclear RNA; tRNA, transfer RNA.

FIG. 3.

Cellular sensor and effector proteins binding viral nucleic acids. (A) Sensing of dsRNAs by MDA5 results in expression of IFN-α/β. These in turn upregulate additional sensors including dsRNA-dependent PKR and OAS1. Binding of PKR to dsRNA phosphorylates the translation initiation factor eIF2-leading to an inhibition of translation and an induction of apoptosis. OAS1 synthesizes 2′-5′-oligoadenylates activating RNASEL. Activation of RNASEL results in RNA degradation and apoptosis. DDX60, ATP-dependent RNA helicase SKIV2L2 (MTR4) and ZCCHC7 promote vRNA degradation via the exosome complex upon virus infection. DDX3 activates IFN signaling and restricts virus replication. (B) Engagement of 5′-triphosphorylated-RNA by RIG-I leads to the expression of type I IFNs, thereby inducing the expression of the effector proteins IFIT1 and IFIT5. Sensing of PPP-RNA by IFIT1 and IFIT5 leads to decreased viral translation and restriction of virus, respectively. vRNA can be recognized and degraded by the exosome cofactors DDX60, MTR4, and ZCCHC7. DDX3, DEAD box protein 3; DDX60, DEAD box protein 60; eIF2, eukaryotic initiation factor 2; IFIT, interferon-induced protein with tetratricopeptide repeats; IFN, interferon; IRFs, interferon regulatory factors; MTR4, ATP-dependent RNA helicase SKIV2L2; OAS1, 2′-5′-oligoadenylate synthetase 1; PKR, double-stranded RNA-dependent protein Protein Kinase R; PPP-RNA, triphosphorylated RNA; vRNA, viral RNA; ZCCHC7, Zinc finger CCHC domain-containing protein 7.