Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155.
MicroRNAs (miRNAs) are small noncoding RNAs that posttranscriptionally regulate gene expression by binding to 3'-untranslated regions (3'UTRs) of target mRNAs. Kaposi's sarcoma-associated herpesvirus (KSHV), a virus linked to malignancies including primary effusion lymphoma (PEL), encodes 12 miRNA genes, but only a few regulatory targets are known. We found that KSHV-miR-K12-11 shares 100% seed sequence homology with hsa-miR-155, an miRNA frequently found to be up-regulated in lymphomas and critically important for B-cell development. Based on this seed sequence homology, we hypothesized that both miRNAs regulate a common set of target genes and, as a result, could have similar biological activities. Examination of five PEL lines showed that PELs do not express miR-155 but do express high levels of miR-K12-11. Bioinformatic tools predicted the transcriptional repressor BACH-1 to be targeted by both miRNAs, and ectopic expression of either miR-155 or miR-K12-11 inhibited a BACH-1 3'UTR-containing reporter. Furthermore, BACH-1 protein levels are low in cells expressing either miRNA. Gene expression profiling of miRNA-expressing stable cell lines revealed 66 genes that were commonly down-regulated. For select genes, miRNA targeting was confirmed by reporter assays. Thus, based on our in silico predictions, reporter assays, and expression profiling data, miR-K12-11 and miR-155 regulate a common set of cellular targets. Given the role of miR-155 during B-cell maturation, we speculate that miR-K12-11 may contribute to the distinct developmental phenotype of PEL cells, which are blocked in a late stage of B-cell development. Together, these findings indicate that KSHV miR-K12-11 is an ortholog of miR-155.
Skalsky
Rebecca L
RL
Department of Molecular Genetics and Microbiology, and Shands Cancer Center, 1376 Mowry Road, Gainesville, FL 32610-3633, USA.
Samols
Mark A
MA
Plaisance
Karlie B
KB
Boss
Isaac W
IW
Riva
Alberto
A
Lopez
M Cecilia
MC
Baker
Henry V
HV
Renne
Rolf
R
D020413:3' Untranslated Regions / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor / Q000737:chemistry / Q000821:virology; D015536:Down-Regulation; D051856:Fanconi Anemia Complementation Group Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D020413:3' Untranslated Regions; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral; D008156:Luciferases