Processing of virus‐derived cytoplasmic primary‐<scp>microRNAs</scp>

Shapiro, Jillian S.

doi:10.1002/wrna.1169

Cited by 12 publications

(10 citation statements)

References 67 publications

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“…Since these proteins that have responsibility for processing pri‐miRNAs are located in the nucleus, virally produced pri‐miRNAs would presumably need to be derived from a nuclear virus. However, this viewpoint is subverted by a recent study that confirmed that a microprocessor containing Drosha of pri‐miRNAs is distributed in the cytoplasm of cells, and cytoplasmic Drosha is involved in processing RNA virus‐derived cytoplasmic pri‐miRNAs (13, 51). Due to the knowledge of noncanonical cytoplasmic pri‐miRNA processing by Drosha, this suggests that the process of a cytoplasmic RNA virus that produces miRNAs is dependent on and is accessible to Drosha.…”

Section: Discussionmentioning

confidence: 99%

Novel microRNA‐like viral small regulatory RNAs arising during human hepatitis A virus infection

et al. 2014

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MicroRNAs (miRNAs), including host miRNAs and viral miRNAs, play vital roles in regulating host-virus interactions. DNA viruses encode miRNAs that regulate the viral life cycle. However, it is generally believed that cytoplasmic RNA viruses do not encode miRNAs, owing to inaccessible cellular miRNA processing machinery. Here, we provide a comprehensive genome-wide analysis and identification of miRNAs that were derived from hepatitis A virus (HAV; Hu/ China/H2/1982), which is a typical cytoplasmic RNA virus. Using deep-sequencing and in silico approaches, we identified 2 novel virally encoded miRNAs, named hav-miR-1-5p and hav-miR-2-5p. Both of the novel virally encoded miRNAs were clearly detected in infected cells. Analysis of Dicer enzyme silencing demonstrated that HAV-derived miRNA biogenesis is Dicer dependent. Furthermore, we confirmed that HAV mature miRNAs were generated from viral miRNA precursors (pre-miRNAs) in host cells. Notably, naturally derived HAV miRNAs were biologically and functionally active and induced post-transcriptional gene silencing (PTGS). Genomic location analysis revealed novel miRNAs located in the coding region of the viral genome. Overall, our results show that HAV naturally generates functional miRNA-like small regulatory RNAs during infection. This is the first report of miRNAs derived from the coding region of genomic RNA of a cytoplasmic RNA virus. These observations demonstrate that a cytoplasmic RNA virus can naturally generate functional miRNAs, as DNA viruses do. These findings also contribute to improved understanding of host-RNA virus interactions mediated by RNA virus-derived

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Section: Discussionmentioning

confidence: 99%

Novel microRNA‐like viral small regulatory RNAs arising during human hepatitis A virus infection

et al. 2014

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“…Recent studies have uncovered a cytoplasmic version of the microprocessor that acts on a viral‐encoded pri‐miRNA, ultimately providing the mature species (termed ‘virtron’) in a Dicer‐dependent manner. The cytoplasmic microprocessor involves Drosha, which is shuttled from the nucleus in a virus‐infection‐dependent manner, but is not strictly dependent upon DGCR8 . Whether Drosha associates with other factors, forming the cytoplasmic microprocessor, remains to be determined.…”

Section: The Ribonuclease III Familymentioning

confidence: 99%

“…The cytoplasmic microprocessor involves Drosha, which is shuttled from the nucleus in a virus-infectiondependent manner, but is not strictly dependent upon DGCR8. [81][82][83] Whether Drosha associates with other factors, forming the cytoplasmic microprocessor, remains to be determined. In a similar light, studies are revealing a broader functional role of DGCR8 in RNA processing pathways that may involve nucleases other than Drosha.…”

Section: Drosha and Microprocessor Functionmentioning

confidence: 99%

Ribonuclease III mechanisms of double‐stranded RNA cleavage

2013

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Double-stranded(ds) RNA has diverse roles in gene expression and regulation, host defense, and genome surveillance in bacterial and eukaryotic cells. A central aspect of dsRNA function is its selective recognition and cleavage by members of the ribonuclease III family of divalent-metal-ion-dependent phosphodiesterases. The processing of dsRNA by RNase III family members is an essential step in the maturation and decay of coding and noncoding RNAs, including miRNAs and siRNAs. RNase III, as first purified from Escherichia coli, has served as a biochemically well-characterized prototype, and other bacterial orthologs provided the first structural information. RNase III family members share a unique fold (RNase III domain) that can dimerize to form a structure that binds dsRNA and cleaves phosphodiesters on each strand, providing the characteristic 2 nt, 3’-overhang product ends. Ongoing studies are uncovering the functions of additional domains, including, inter alia, the dsRNA-binding and PAZ domains that cooperate with the RNase III domain to select target sites, regulate activity, confer processivity, and support the recognition of structurally diverse substrates. RNase III enzymes function in multicomponent assemblies that are regulated by diverse inputs, and at least one RNase III-related polypeptide can function as a non-catalytic, dsRNA-binding protein. This review summarizes the current knowledge of the mechanisms of catalysis and target site selection of RNase III family members, and also addresses less well understood aspects of these enzymes and their interactions with dsRNA.

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“…However, recent studies have showed that a noncanonical microprocessor containing Drosha and pri-miRNAs is distributed in the cytoplasm in virus-infected cells. Moreover, cytoplasmic Drosha is involved in processing RNA virus-derived pri-miRNAs [38], which suggests PRRSV, a cytoplasmic RNA virus, may utilize the cellular miRNA processing machinery to produce vsRNAs. Furthermore, a putative non-canonical Ago2-dependent or RNase L-dependent pathway has been reported to generate functional small RNA from a cytoplasmic RNA virus [24, 28].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-like viral small RNA from porcine reproductive and respiratory syndrome virus negatively regulates viral replication by targeting the viral nonstructural protein 2

Yan

Zhang

et al. 2016

Oncotarget

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Many viruses encode microRNAs (miRNAs) that are small non-coding single-stranded RNAs which play critical roles in virus-host interactions. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically impactful viruses in the swine industry. The present study sought to determine whether PRRSV encodes miRNAs that could regulate PRRSV replication. Four viral small RNAs (vsRNAs) were mapped to the stem-loop structures in the ORF1a, ORF1b and GP2a regions of the PRRSV genome by bioinformatics prediction and experimental verification. Of these, the structures with the lowest minimum free energy (MFE) values predicted for PRRSV-vsRNA1 corresponded to typical stem-loop, hairpin structures. Inhibition of PRRSV-vsRNA1 function led to significant increases in viral replication. Transfection with PRRSV-vsRNA1 mimics significantly inhibited PRRSV replication in primary porcine alveolar macrophages (PAMs). The time-dependent increase in the abundance of PRRSV-vsRNA1 mirrored the gradual upregulation of PRRSV RNA expression. Knockdown of proteins associated with cellular miRNA biogenesis demonstrated that Drosha and Argonaute (Ago2) are involved in PRRSV-vsRNA1 biogenesis. Moreover, PRRSV-vsRNA1 bound specifically to the nonstructural protein 2 (NSP2)-coding sequence of PRRSV genome RNA. Collectively, the results reveal that PRRSV encodes a functional PRRSV-vsRNA1 which auto-regulates PRRSV replication by directly targeting and suppressing viral NSP2 gene expression. These findings not only provide new insights into the mechanism of the pathogenesis of PRRSV, but also explore a potential avenue for controlling PRRSV infection using viral small RNAs.

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Processing of virus‐derived cytoplasmic primary‐microRNAs

Cited by 12 publications

References 67 publications

Novel microRNA‐like viral small regulatory RNAs arising during human hepatitis A virus infection

Novel microRNA‐like viral small regulatory RNAs arising during human hepatitis A virus infection

Ribonuclease III mechanisms of double‐stranded RNA cleavage

MicroRNA-like viral small RNA from porcine reproductive and respiratory syndrome virus negatively regulates viral replication by targeting the viral nonstructural protein 2

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