Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators

Abstract

In latently infected marmoset T cells, H erpesvirus saimiri (HVS) is a T-lymphotropic gammaherpesvirus that causes acute T-cell lymphomas and leukemias inNew World primates and transforms human primary T cells in vitro (1). The most abundant transcripts in HVS latently infected marmoset T cells are seven noncoding U-rich RNAs, known as HSURs (H. saimiri U-rich RNAs) (2). The functions of these viral noncoding RNAs are not well understood. HSUR1 forms base-pairing interactions with a host microRNA (miRNA), miR-27, targeting it for rapid degradation (3). This helps to promote constitutive activation of infected T cells and viral latency (4, 5). We recently discovered that, in addition to the HSURs, HVS expresses during latency another class of noncoding RNAs: six miRNAs called miR-HSURs (6). The miR-HSURs are cotranscribed together with the HSURs to give rise to chimeric primary transcripts, which are then processed via a combination of canonical and noncanonical pathways to yield mature HSURs and miRNAs (6).In complex with Argonaute (Ago) family proteins, mature miRNAs modulate target protein levels through base pairing with their mRNAs (7). Like cellular miRNAs, viral miRNAs play key regulatory roles in gene expression in host cells (8). Previous studies suggested that viral miRNAs benefit infection and the viral life cycle through regulation of (i) viral persistence, (ii) proliferation and/or survival of the infected host cells, and (iii) host immune evasion (2). Because the functions of the miR-HSURs were unknown, we embarked on the identification of their viral and cellular targets in latently infected marmoset T cells. MATERIALS AND METHODSCell culture and transfection. Marmoset (Callithrix jacchus) T cells infected with HVS strain ⌬2A (referred to as ⌬2A cells) were generated and grown as described previously (9). They were derived from marmoset peripheral blood lymphocytes immortalized by HVS and are predominantly activated CD8 cytotoxic T cells. A 1,379-bp deletion present in the

MicroRNA Involvement in Signaling Pathways During Viral Infection

“…As a result, in the beginning of our classification we could divide them into host miRNAs and viral miRNAs, according to their source (Table 1). Similar to host miRNAs, the viral ones participate in the life cycle of the virus and could induce certain modifications in the host cells (Guo et al, 2015;Bruscella et al, 2017). Likewise, they are also processed by the previously mentioned RNases Drosha and Dicer, although some viral miRNAs have been described to skip the first step and pass directly to Dicer processing (Bogerd et al, 2010;Diebel et al, 2010;Tycowski et al, 2015).…”

MicroRNAs in large herpesvirus DNA genomes: recent advances

“…Similarly, miR-US25-1-5p encoded by hCMV was shown to target multiple cellular genes to inhibit viral replication (63). Further supporting the role of Multiple components of the host secretory pathway Immune evasion (reduced cytokine secretion) (100) herpesvirus miRNAs in restraining reactivation, a recent report has shown that miR-HSUR4-3p present in the herpesvirus saimiri (HVS) U-rich RNAs (HSURs) could repress the expression of the p300 transcriptional coactivator by binding the open reading frame of its mRNA (64).…”

“…Interestingly, HVS miR-HSUR5-3p downregulated WEE1, a negative regulator of cell cycle progression, leading to reduced phosphorylation of its substrate, cyclin-dependent kinase (CDK1) (64). Furthermore, several studies have shown the potential role of some EBV and hCMV miRNAs in inhibiting cell apoptosis through restriction of expression of pro-apoptotic proteins (66)(67)(68)(69).…”

“…As EBV and KSHV were shown to encode miRNAs targeting MICB (106), this mechanism might be conserved in the Herpesviridae family. In addition, HVS miR-HSUR5-3p could regulate BiP, a chaperone facilitating maturation of MHC class I molecules in the endoplasmic reticulum (64), and hCMV miR-US4-1 was reported to downregulate antigen loading on MHC class I in infected cells through targeting the endoplasmic reticulum aminopeptidase ERAP1b (107).…”

Long noncoding RNAs: Novel regulators of virus‐host interactions

“…In addition, a 3.91 kb lncRNA M3‐04 generated by gammaherpesviruses regulates viral replication in mice by interacting with antisense miRNAs and the latency gene M2 . Other herpesviruses also encode multiple functional lncRNAs, such as the Epstein‐Barr virus encoding ncRNA, BamH I‐A rightward transcripts, Kaposi's sarcoma‐associated herpesvirus (KSHV) encoding UCA1 , and herpesvirus saimiri encoding U‐rich RNAs . Additionally, the 3′‐untranslated region (UTR) of the flavivirus RNA genome is capable of transcribing an active lncRNA, termed the subgenomic flavivirus RNA (sfRNA), which protects viral RNAs from degradation by the host nuclease Xrn1 and suppresses antiviral RNA interference (RNAi) in infected human cells in culture and, also, interestingly, in mosquitoes by direct interaction with the RNAi machinery .…”