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Review
, 227 (1), 176-88

RNA-based Viral Immunity Initiated by the Dicer Family of Host Immune Receptors

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Review

RNA-based Viral Immunity Initiated by the Dicer Family of Host Immune Receptors

Roghiyh Aliyari et al. Immunol Rev.

Abstract

Suppression of viral infection by RNA in a nucleotide sequence homology-dependent manner was first reported in plants in early 1990 s. Studies in the past 15 years have established a completely new RNA-based immune system against viruses that is mechanistically related to RNA silencing or RNA interference (RNAi). This viral immunity begins with recognition of viral double-stranded or structured RNA by the Dicer nuclease family of host immune receptors. In fungi, plants and invertebrates, the viral RNA trigger is processed into small interfering RNAs (siRNAs) to direct specific silencing of the homologous viral genomic and/or messenger RNAs by an RNaseH-like Argonaute protein. Deep sequencing of virus-derived siRNAs indicates that the immunity against viruses with a positive-strand RNA genome is induced by Dicer recognition of dsRNA formed during the initiation of viral progeny (+)RNA synthesis. The RNA-based immune pathway in these organisms overlaps the canonical dsRNA-siRNA pathway of RNAi and may require amplification of viral siRNAs by host RNA-dependent RNA polymerase in plants and nematodes. Production of virus-derived small RNAs is undetectable in mammalian cells infected with RNA viruses. However, infection of mammals with several nucleus-replicating DNA viruses induces production of virus-derived microRNAs capable of silencing host and viral mRNAs as found for viral siRNAs. Remarkably, recent studies indicate that prokaryotes also produce virus-derived small RNAs known as CRISPR RNAs to guide antiviral defense in a manner that has yet to be defined. In this article, we review the recent progress on the identification and mechanism of the key components including viral sensors, viral triggers, effectors, and amplifiers, of the small RNA-directed viral immunity. We also highlight some of the many unresolved questions.

Figures

Fig. 1
Fig. 1
Domain structures of representatives from the three classes of RNase III.
Fig. 2
Fig. 2. Crystal structure of Giardia Dicer
Depicted are the PAZ (Piwi/Argonaute/Zwille) domain (orange), the connector helix (red), the RNase IIIa domain (yellow), and the RNase IIIb domain (green). Reprinted from (11).
Fig. 3
Fig. 3
Structures of the bipartite (+)RNA genome and virions of Flock house virus.
Fig. 4
Fig. 4
Structures of the (+)RNA genomes of cucumber mosaic virus (CMV) and turnip crinkle virus (TCV).
Fig. 5
Fig. 5. Model for the induction and suppression of the Dicer-initiated viral immunity in Drosophila against Flock house virus
Asymmetric RNA synthesis in the replication of (+)RNA viruses involves multiple initiation of the progeny (+)RNA synthesis on the low abundant (-)RNA template complexed with the viral RdRP and other host factors. The resulting dsRNA of approximate 400 nt in length formed between the 5′-terminal nascent progeny (+)RNA1 and the (-)RNA1 template in FHV-infected cells, termed the initiating vRI-dsRNA, serves as substrates of DCR2. This results in the predominant production of 5′-terminal viRNAs, thereby triggering the RNAi-mediated viral immunity and abortive infection by FHV-ΔB2. In addition to binding to viRNAs, B2 is part of the viral RNA replication complex by direct interactions with viral RdRP (protein A) and vRI-dsRNA and inhibits DCR2-dependent production of viRNAs, thus ensuring successful infection by FHV. We propose that sequestering the initiating vRI-dsRNA and inhibiting their processing into the 5′-terminal viRNAs by B2 play a particularly important role in the suppression of the viral immunity. Reprinted from (32). RdRP, RNA-dependent RNA polymerase; FHV, Flock house virus; DCR, Dicer.
Fig. 6
Fig. 6. A framework of the Dicer-initiated viral immunity
The immunity begins with the recognition of the viral triggering RNA molecules by the viral sensor (Dicer) of the host. The products of Dicer, the virus-derived small RNAs, are loaded in Argonaute protein-containing effector complexes to guide cleavage or translational arrest of viral RNAs. In plants and Caenorhabditis elegans, virus-derived siRNAs may be further amplified by a host RNA-dependent RNA polymerase (RdRP).

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