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Review
, 253 (1), 97-111

RNA-based Mechanisms Regulating Host-Virus Interactions

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Review

RNA-based Mechanisms Regulating Host-Virus Interactions

Rui Zhou et al. Immunol Rev.

Abstract

RNA interference (RNAi) is an ancient process by which non-coding RNAs regulate gene expression in a sequence-specific manner. The core components of RNAi are small regulatory RNAs, approximately 21-30 nucleotides in length, including small interfering RNAs (siRNAs) and microRNAs (miRNAs). The past two decades have seen considerable progress in our understanding of the molecular mechanisms underlying the biogenesis of siRNAs and miRNAs. Recent advances have also revealed the crucial regulatory roles played by small RNAs in such diverse processes as development, homeostasis, innate immunity, and oncogenesis. Accumulating evidence indicates that RNAi initially evolved as a host defense mechanism against viruses and transposons. The ability of the host small RNA biogenesis machinery to recognize viral double-stranded RNA replication intermediates and transposon transcripts is critical to this process, as is small RNA-guided targeting of RNAs via complementary base pairing. Collectively, these properties confer unparalleled specificity and precision to RNAi-mediated gene silencing as an effective antiviral mechanism.

Figures

Fig. 1
Fig. 1. Outline of the siRNA and miRNA pathways in Drosophila
Exogenous dsRNAs (viral RNA replication intermediates or experimental reagents) or endogenous dsRNAs (structured transcripts, transposon transcripts, and convergently transcribed mRNAs that hybridize) are processed by the Dcr-2/Loqs-PD complex into siRNAs, which are then incorporated into AGO2-containing siRISCs in a Dcr-2/R2D2-dependent manner. There, siRNAs target mRNAs by complementary base pairing, which leads to degradation of the target mRNA. Primary miRNA transcripts are processed in the nucleus by the Drosha/Pasha complex into pre-miRNAs, which are subsequently exported to the cytoplasm by Exportin 5/Ran-GTP and further processed by the Dcr-1/Loqs-PB complex into miRNA duplexes. The miRNA strands are selectively incorporated into AGO1-containing miRISCs, where they target mRNAs via complementary base pairing between the miRNA seed sequence and miRNA-binding sites in target mRNAs, leading to translation inhibition and target mRNA destabilization.
Fig. 2
Fig. 2. Gene silencing pathways in mammals
In oocytes and embryonic stem cells, dsRNAs are formed by hybridization between antisense pseudogenic transcripts and spliced genic mRNAs or between sense and antisense transposon transcripts. The dsRNAs are processed by Dicer into siRNAs, which are then incorporated into AGO2-containing siRISCs where they silence the expression of complementary target mRNAs or transposon transcripts via the slicer activity of AGO2. Guide strand perfectly matches the accessible sites in a target mRNA (178), forming an A-form helix required for the slicer activity of AGO2 (179-181). In all cell and tissue types, primary miRNA transcripts are processed in the nucleus by the Drosha/DGCR8 complex into pre-miRNAs, which are exported to the cytoplasm by Exportin 5/Ran-GTP and further processed into miRNA duplexes by the DCR-1/TRBP complex. The miRNA strand of the duplex is randomly partitioned among the four AGO proteins to form miRISCs. miRNAs guide the targeting of mRNAs via complementary base pairing between the miRNA seed sequence and miRNA-binding sites in target mRNAs, leading to translation inhibition, localization to cytoplasmic structures P bodies (182), and target mRNA destabilization (183).
Fig. 3
Fig. 3. Viral suppressors of RNAi impinge on various steps in RNAi
DCV-1A selectively associates with long dsRNAs and inhibits Dcr-2–mediated processing of viral dsRNAs into vsiRNAs. FHV-B2 binds both siRNAs and long dsRNAs, thereby inhibiting Dcr-2–mediated viral dsRNA destruction and the loading of vsiRNAs into AGO2. CrPV-1A associates with AGO2 and inhibits its slicer activity, thereby impairing the effector step of RNAi.
Fig 4
Fig 4. Plausible mechanisms for modulation of host-virus interactions by miRNAs
Viruses encode miRNA genes and use the host RNAi machinery to assemble viral RISCs that can target host and viral mRNAs. Viral infections also affect the expression of cellular miRNAs and the concentrations of specific miRISCs. Cellular RISCs can target viral mRNAs as part of the host antiviral response. RISCs suppress translation and localize mRNA-RISC RNPs to P bodies. Depending on the prevailing cellular conditions, the suppressed mRNAs may be destroyed or re-enter the translation process. Another mechanism (not shown) could use cellular RISCs to suppress cellular mRNAs integral to the host antiviral response, which would allow the virus to evade the immune response.

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