Processing of virus‐derived cytoplasmic primary‐microRNAs

Focus Article

Jillian S. Shapiro

Published Online: May 28 2013

DOI: 10.1002/wrna.1169

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MicoRNAs (miRNAs) are small noncoding RNAs that associate with Argonaute (AGO) family member proteins to mediate silencing of host mRNA transcripts. A number of DNA viruses and a single retrovirus exploit this pathway to generate their own miRNAs in an effort to self regulate or combat the host immune response to infection. While natural examples of viral miRNAs have been limited to nuclear viruses, manipulation of cytoplasmic‐restricted RNA virus genomes revealed the ability of these vectors to produce abundant levels of mature, functional miRNAs, exclusively within the cytoplasm. This novel processing mechanism is found to be dependent upon the ribonuclease (RNAse) III proteins Drosha and Dicer, while processing is able to proceed in the absence of the canonical dsRNA binding proteins DiGeorge syndrome critical region gene 8 (DGCR8), Tar RNA binding protein 2 (TRBP2), and protein kinase R activating protein (PACT). Processing of cytoplasmic restricted primary‐miRNA transcripts (c‐pri‐miRNAs) corresponds with virus‐induced redistribution of Drosha, implicating the formation of a noncanonical microprocessor. This review will discuss c‐pri‐miRNA processing, the mechanism of miRNA production, and the implications of a virus‐induced cytoplasmic microprocessor. WIREs RNA 2013, 4:463–471. doi: 10.1002/wrna.1169 This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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Proposed mechanism of c‐pri‐miRNA processing. (1) SINV infection leads to Drosha relocalization and the production of c‐pri‐miRNAs within the cytoplasm; (2) Drosha mediates the cytoplasmic cleavage of c‐pri‐miRNAs, releasing a pre‐miRNA that is (3) processed by Dicer. (4) One strand of the duplex is loaded into RISC where it (5) mediates post‐transcriptional silencing.

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Small RNA pathways in insects and mammalians. In Drosophila melanogaster, virus‐derived dsRNA is cleaved by Dicer‐2 in to duplex RNAs, one strand of which mediates the targeting of pathogen RNA. In mammalians, miRNAs are produced in a stepwise fashion, via Drosha and Dicer, to produce a small RNA that mediates silencing of host transcripts.

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