RNA-virus ja mikroRNA

https://link.springer.com/article/10.1186/s41544-019-0037-6

An overview of RNA virus-encoded microRNAs

• Xihan Li &
• Xiaoping Zou 

ExRNA volume 1, Article number: 37 (2019) Cite this article

Abstract

MicroRNAs (miRNAs) are a number of small non-coding RNAs playing a regulatory part in gene expression. Many virus-encoded miRNAs have been found, which manifests that viruses as well apply the basic pattern of gene regulation, however, mostly in viruses transcribed from double-stranded DNA genomes  (dsDNA) . It is still in dispute if RNA viruses could encode miRNAs because the excision of miRNA might result in the cleavage of viral RNA genome. We will focus on the miRNAs encoded by RNA virus and discuss their potential role in viral replication cycle and host cells.

Discovery and biogenesis of microRNAs

MicroRNAs (miRNAs) are a number of small noncoding RNAs which typically silence the expression of genes via various mechanisms [1,2,3]. MiRNAs are key factors in regulating gene expression of various cellular processes, so the discovery of miRNAs turns out to be a noteworthy breakthrough of molecular biology [4,5,6,7,8].

 In 1993, there had been researchers observed MiRNA lin-4 in the Caenorhabditis elegans [2, 8]. In subsequent researches, other similar small regulatory RNAs were discovered in various organisms. It has been illustrated that the small RNA originated from a hairpin structure which are partly complementary to the 3 ‘untranslated regions (UTR) of other target transcripts [9]. MRNA destabilization and translational repression can be triggered by this binding, resulting in protein production decline [10, 11].

 MiRNAs are estimated to have an influence on 60% of mammalian gene expression [12]. Recent studies indicate that miRNAs produce main effect in various regulatory pathways, for instance metabolism, apoptosis, proliferation and differentiation of cells, embryonic development, cancer, and so on [13, 14].

In mammals, miRNAs are created in a multi-step process. The biogenesis pathway of miRNA has been studied in detail.

Canonical miRNAs derived from hairpin-shaped transcripts (pri-miRNAs) which are usually transcribed by RNA polymerase II (pol II) [15]. Then the precursor miRNAs (pre-miRNAs) are cleaved out of the larger pri-miRNA by the RNAse III-like endonuclease Drosha[16]. The pri-miRNA is conducted via the nuclear microprocessor complex, which comprises the double-stranded RNA (dsRNA)-discerning DiGeorge-syndrome critical-region protein 8 (DGCR8) and endonuclease Drosha [17].
 Then the hairpin pre-miRNA is carried out of the nucleus by the nuclear transport receptor, Exportin-5 (XPO5, https://www.genecards.org/cgi-bin/carddisp.pl?gene=XPO5&keywords=Exportin-5)
and finally to the cytoplasm [18, 19]. Then in the presence of RNAse III-like endonuclease Dicer, the pre-miRNAs are cleaved after entering into the cytoplasm [20]. A short duplex RNA is generated by dicer-mediated cleavage. Over the RNA-induced silencing complex (RISC) activation process, one strand of the duplex called miRNA, remains stably combined into the complex (RISC*) and undertakes as a sequence-specific probe targeting RISC* to the complementary mRNA [21]. Another strands, is released, degraded and partly complementary target sequences [22].

Virus-encoded microRNAs

As intracellular pathogens, viruses are related to a lot of diseases in plants and animals. Normally viruses use the biosynthetic molecular mechanism to multiply in host cell. Not surprisingly, viruses can generate miRNAs in their own genomes as well, which may generally take advantage of the host gene expression. Shortly after the first miRNA was identified, the first virus-encoded miRNAs was discovered for the human Epstein-Barr virus (EBV) [23]. Up to now, more than 250 novel viral miRNAs were discovered, which provides the possibility to explore the function and biogenesis of virus-encoded miRNAs [24]. Although the function of miRNAs in DNA virus has been described in detail, yet if RNA viruses could encode miRNAs is less understood.

A possible explanation is that most RNA virus duplicates in cytoplasm and the viral RNAs could not interact with the nuclear microprocessor complex mediating the biosynthesis of miRNA [25, 26]. Another reason is the processing of miRNAs from the viral genome will destroy the viral RNA then impact the replication of virus [25, 27]. Viruses, however, are able to alter cellular pathways out of their self-interest, several researches employed ultra-sensitive mechanisms to discover miRNAs encoded by RNA virus [28, 29]. We describe the features of miRNAs encoded by RNA virus as well as their underlying biological function involved in gene regulation. An over-view of miRNAs encoded by RNA viruses is given in Table 1.

MicroRNA-like small RNA encoded by H5N1 influenza virus

H5N1 influenza virus, a single-stranded and negative-sense RNA, leads to the highest mortality in all influenza viruses [53]. It is reported that H5N1 influenza virus generates a microRNA-like small RNA, which was named miR-HA-3p. MiR-HA-3p is produced out of a stem loop-including viral RNA precursor cleaved by Ago 2 using Solexa sequencing, qRT-PCR assays and northern blot [54]. Further research demonstrates that the suppression of poly (rC)-binding protein 2 (PCBP2), which is an negative regulator of RIG-I/MAVS regulated by miR-HA-3p could induce ‘cytokine storm’ in H5N1 virus infected macrophages of mice and human. This discovery provides a possibly efficient treatment strategy to deal with H5N1 infection, which is based on antagomir-HA-3p.