Abstract
Recent research raised the possibility that some viral microRNAs (miRNAs) may function as orthologs of cellular miRNAs. In the present work, to study the functional orthologous relationships of viral and cellular miRNAs, we first constructed a dual-fluorescent protein reporter vector system for the easy determination of miRNA function. By expressing the miRNAs and the indicator and internal control fluorescent proteins individually from a single vector, this simple reporter system can be used for miRNA functional assays that include visualizing miRNA activity in live cells. Sequence alignments indicated that the simian virus 40 (SV40) encoded miRNA sv40-mir-S1-5p contains a seed region identical to that of the human miRNA hsa-miR423-5p. Using the new reporter system, it was found that sv40-mir-S1-5p and hsa-miR423-5p downregulate the expression of common artificial target mRNAs and some predicted biological targets of hsa-miR423-5p, demonstrating that they are functional orthologs. The human immunodeficiency virus 1 (HIV-1) encoded hiv1-miR-N367 also contains a seed sequence identical to that of the human miRNA hsa-miR192. Functional assays showed that hiv1-miR-N367 and hsa-miR192 could downregulate common artificial and predicted biological targets, suggesting that these miRNAs may also act as functional orthologs. Thus, this study presents a simple and universal system for testing miRNA function and identifies two new pairs of functional orthologs, sv40-mir-S1-5p and hsa-miR423-5p as well as hiv-1-miR-N367 and hsa-miR192. These findings also expand upon our current knowledge of functional homology and imply that a more general phenomenon of orthologous relationships exists between viral and cellular miRNAs.
Highlights
MicroRNAs are a class of small regulatory RNAs that are expressed in eukaryotes and viruses ([1,2,3]; reviewed by [4,5]). miRNAs play vital roles in post-transcriptional regulation of gene expression, participating in multiple cellular biological processes or in the viral replication cycle [4,5]
Cellular miRNAs repress the expression of specific mRNAs by base pairing by the miRNA ‘‘seed region’’ to the 39-untranslated region (39-UTR) of target mRNAs [4]
To find new virus-encoded miRNAs that may act as orthologs of cellular miRNAs, we examined the miRNAs encoded by the DNA virus Simian Virus 40 (SV40) and the RNA virus Human Immunodeficiency Virus-1 (HIV–1) for any sequence homologies with human-derived miRNAs listed in miRBase
Summary
MicroRNAs (miRNAs) are a class of small regulatory RNAs (approximately 18 to 24 nucleotides in length) that are expressed in eukaryotes and viruses ([1,2,3]; reviewed by [4,5]). miRNAs play vital roles in post-transcriptional regulation of gene expression, participating in multiple cellular biological processes or in the viral replication cycle [4,5]. Viral miRNAs could repress host cellular genes and viral genes to benefit viral replication by employing both miRNA and siRNA (small interfering RNA) pathways [6,7,8]. Several recent publications have raised the new idea that viral miRNAs act as functional orthologs of cellular miRNAs [9,10,11]. These orthologs may play complex roles in virus-host interactions. Until now, only one cellular miRNA, miR155, has been verified to be a functional ortholog of some viral miRNAs [9,10,11]. It remains uncertain whether there are other cellular and viral miRNAs orthologous pairs, which would imply that this represents a more general phenomenon
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