Emerging themes from EBV and KSHV microRNA targets

Abstract

EBV and KSHV are both gamma-herpesviruses which express multiple viral microRNAs. Various methods have been used to investigate the functions of these microRNAs, largely through identification of microRNA target genes. Surprisingly, these related viruses do not share significant sequence homology in their microRNAs. A number of reports have described functions of EBV and KSHV microRNA targets, however only three experimentally validated target genes have been shown to be targeted by microRNAs from both viruses. More sensitive methods to identify microRNA targets have predicted approximately 60% of host targets could be shared by EBV and KSHV microRNAs, but by targeting different sequences in the host targets. In this review, we explore the similarities of microRNA functions and targets of these related viruses.

Keywords: EBV; HHV4; HHV8; KSHV; miRNAs; microRNAs.

Figure 1

Venn diagram of BC1 predicted miRNA targets from Gottwein et al. 2011.

Figure 2

Venn diagram of BC1 predicted miRNA targets from Gottwein et al. 2011.

Figure 3

Map of interferon receptor 2 (IFNAR2) 3’UTR with miRNA target sites as determined by CLIP assays.

Figure 4

KSHV- and EBV-encoded miRNAs target several key pathways to establish disease. 1) Viral miRNAs can inhibit pro-apoptotic proteins like Bim and BCLAF1. 2) Viral miRNAs can also enable the infected cells to evade recognition by the immune system by repressing either the T-cell attracting chemokine, CXCL-11 or the NK-cell attracting ligand, MICB. 3) miRNAs can also inhibit the production of interferons and inflammatory cytokines by repressing factors like IKKε, IRAK1 and MyD88. 4) By repressing factors like IκBα and Dicer, viral miRNAs can also regulate latency. In addition to cellular targets, the RTA protein of KSHV that acts as the master regulator of the latency-lytic switch, is itself a target of KSHV miRNAs. 5) Several transcription factors like BACH1, c/EBPβ and p53 are repressed by KSHV and EBV miRNAs. 6) KSHV miRNAs repress p21 and SMAD5 to overcome p21- and TGFβ- mediated growth arrest, respectively. In this illustration, the targets of KSHV miRNAs are in green, those of EBV miRNAs are in blue and targets that are repressed by both KSHV and EBV are underlined. The dotted line represents a viral target of KSHV-encoded miRNAs.