Kaposi's Sarcoma-Associated Herpesvirus microRNAs

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human pathogenic γ-herpesvirus strongly associated with the development of Kaposi's Sarcoma and B cell proliferative disorders, including primary effusion lymphoma (PEL). The identification and functional investigation of non-coding RNAs expressed by KSHV is a topic with rapidly emerging importance. KSHV miRNAs derived from 12 stem-loops located in the major latency locus have been the focus of particular attention. Recent studies describing the transcriptome-wide identification of mRNA targets of the KSHV miRNAs suggest that these miRNAs have evolved a highly complex network of interactions with the cellular and viral transcriptomes. Relatively few KSHV miRNA targets, however, have been characterized at a functional level. Here, our current understanding of KSHV miRNA expression, targets, and function will be reviewed.

Keywords: KSHV; herpesvirus; microRNA.

Figure 1

miRNA biogenesis and target recognition. (A) Schematic of the canonical miRNA biogenesis pathway. pri-miRNAs are typically capped and polyadenylated and contain one or more miRNA stem-loops at exonic or intronic locations. The pre-miRNA stem-loop is excised by the microprocessor complex, containing the endonuclease Drosha and its cofactor DiGeorge syndrome critical region gene 8 (DGCR8), which helps position Drosha. Following nuclear export, the pre-miRNA is processed by Dicer to a miRNA:passenger strand duplex. Dicer processing is closely coupled to loading of the mature miRNA into the RISC. RISC complexes contain one of four Ago proteins (Ago1–4), which bind the miRNA, and associated proteins, including TNRC6. (A)_n indicates the position of the polyA tail and arrows indicate cleavage sites. (B) Shown are the minimal 7mer-m8 (top) and 7mer-1A (bottom) seed-mediated interactions between a miRNA (nts are numbered from the 5′ end of the miRNA) and its mRNA target.

Figure 2

The KSHV miRNAs are expressed from the major latency locus. (A) Schematic of the latency locus and the adjacent K14 and ORF74 genes. The LANA, v-cyclin, v-FLIP, and Kaposin A and B open reading frames (ORFs) are indicated by black arrows. The Kaposin C ORF includes the ORF of Kaposin A and an N-terminal extension (white box). Pre-miRNA sequences are indicated by numbered red arrows. Overlapping DNA elements are indicated by gray boxes. Also shown is the antisense to latency locus transcript (ALT). (B) Schematic of the KSHV pri-miRNAs, showing exons (thick lines), introns, transcription start sites. In both panels, nucleotide coordinates refer to positions in the KSHV genome (GenBank accession number: U75698.1). Double arrows indicate transcription start site of lytic RNAs, single arrows start sites of latent RNAs. The bottom transcript was detected in BC-1 cells, but not in BCBL-1 cells. (A,B) are drawn approximately to scale and aligned to each other.

Figure 3

(A) KSHV miRNAs with known or potential cellular analogs. miRNAs are aligned to show seed (red) and non-seed (blue) homologies. (B) Schematic illustrating the origin of moRNAs.