Virus Meets Host MicroRNA: the Destroyer, the Booster, the Hijacker

Epstein-Barr virus (EBV)is an oncogenic human herpesvirus involved in the pathogenesis of Burkitt's lymphoma (BL) and various other lymphoproliferative disorders. In BL, EBV protein expression is restricted to EBV nuclear antigen 1 (EBNA1), but small noncoding RNAs such as EBV-encoded small RNAs (EBERs) and microRNAs (miRNAs) can also be detected. miRNAs play major roles in crucial processes such as proliferation, differentiation, and cell death. It has recently become clear that alterations in the expression profile of miRNAs contribute to the pathogenesis of a number of malignancies. During latent infection, EBV expresses 25 viral pre-miRNAs and modulates the expression of specific cellular miRNAs, such as miR-155 and miR-146, which potentially play a role in oncogenesis. Here, we established the small-RNA expression profiles of three BL cell lines. Using largescale sequencing coupled to Northern blotting and real-time reverse transcription-PCR (RT-PCR) analysis validation, we demonstrated the differential expression of some cellular and viral miRNAs. High-level expression of the miR-183-96-182 cluster and EBV miR-BamHI A rightward transcript (miR-BART) cluster was significantly associated with EBV type I latency. This expression was not affected by viral reactivation since transforming growth factor ␤1 (TGF-␤1) stimulation did not significantly change the miRNA profiles. However, using several approaches, including de novo infection with a mutant virus, we present evidence that the expression of latent membrane protein 1 (LMP-1) triggered downregulation of the expression of the miR-183-96-182 cluster. We further show that this effect involves the Akt signaling pathway. IMPORTANCEIn addition to expressing their own miRNAs, herpesviruses also impact the expression levels of cellular miRNAs. This regulation can be either positive or negative and usually results in the perturbation of pathways to create a cellular environment that is more "virus-friendly." For example, EBV induces the expression of miR-155, a well-characterized oncomiR, which leads to increased cell proliferation and decreased cell death. Here, we show that EBV-encoded LMP-1 is also involved in the downregulation of a cluster of three miRNAs, miR-183, -96, and -182, which are known to be also repressed in several cancers. We therefore identify yet another potential player in EBV-induced oncogenesis. M ore than 90% of adults worldwide are infected with the Epstein-Barr virus (EBV), a member of the herpesvirus family (1). EBV is linked to the development of various lymphocyte malignancies, including Burkitt's lymphoma (BL), Hodgkin disease (HD), NK/T tumors, and lymphoproliferations linked to immunosuppression, including posttransplant lymphoproliferative disorders (PTLD) and AIDS-associated lymphomas (2). EBV mostly establishes a latent infection in its target cells. The expression pattern of latent genes allows distinguishing among three different latency types termed latency I to latency III. Latency III is characterized by the expressi...

Section: Discussionmentioning

confidence: 99%

Modulation of MicroRNA Cluster miR-183-96-182 Expression by Epstein-Barr Virus Latent Membrane Protein 1

Oussaief

Fendri

Chane-Woon-Ming

et al. 2015

“…Thus, miRNAs play an important role in regulating the cellular developmental processes and the immune response, that is, the miRNAs not only play important roles in cell differentiation (4,5), proliferation (6,7), metabolism (8,9), and apoptosis (10,11) but also play critical roles in the regulation of innate and adaptive immune responses (12,13). Thus, it is not surprising that many viruses could alter the expression profile of host cellular miRNA to modulate innate and adaptive antiviral immunity and to facilitate viral replication or escape from host clearance (14)(15)(16)(17).…”

mentioning

confidence: 99%

MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction

Chen

Shi

Zhang

et al. 2017

MicroRNAs (miRNAs) play an important role in the regulation of immune responses. Previous studies have indicated that dysregulating the miRNAs leads to the immunosuppression of porcine reproductive and respiratory syndrome virus (PRRSV). However, it is not clear how PRRSV regulates the expression of host miRNA, which may lead to immune escape or promote the replication of the virus. The present work suggests that PRRSV upregulated the expression of miR-373 through elevating the expression of specificity protein 1 (Sp1) in MARC-145 cells. Furthermore, this work demonstrated that miR-373 promoted the replication of PRRSV, since miR-373 was a novel negative miRNA for the production of beta interferon (IFN-␤) by targeting nuclear factor IA (NFIA), NFIB, interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and interferon regulatory factor 1 (IRF1). We also found that both NFIA and NFIB were novel proteins for inducing the production of IFN-␤, and both of them could inhibit the replication of PRRSV. In conclusion, PRRSV upregulated the expression of miR-373 by elevating the expression of Sp1 and hijacked the host miR-373 to promote the replication of PRRSV by negatively regulating the production of IFN-␤.IMPORTANCE PRRSV causes one of the most economically devastating diseases of swine, and there is no effective method for controlling PRRSV. It is not clear how PRRSV inhibits the host's immune response and induces persistent infection. Previous studies have shown that PRRSV inhibited the production of type I IFN, and the treatment of type I IFN could efficiently inhibit the replication of PRRSV, so it will be helpful to design new methods of controlling PRRSV by understanding the molecular mechanism by which PRRSV modulated the production of IFN. The current work shows that miR-373, upregulated by PRRSV, promotes PRRSV replication, since miR-373 impaired the production of IFN-␤ by targeting NFIA, NFIB, IRAK1, IRAK4, and IRF1, and both NFIA and NFIB were antiviral proteins to PRRSV. In conclusion, this paper revealed a novel mechanism of PRRSV that impaired the production of type I IFN by upregulating miR-373 expression in MARC-145 cells.

“…Similarly, miR-103/107 isoforms, also 1 nt shorter at their 5= ends, can form seed (nt 2 to 8) base-pairing interactions (with a partially overlapping binding site for miR-HSUR5-3p) within the miR-HSUR5-3p-Ago cluster number 2 on the WEE1 3= UTR. Viruses have evolved strategies to boost repression of some host mRNAs to benefit infection (5). For example, several oncogenic herpesviruses express homologs of host miR-155; these viral miRNAs share the seed sequence with miR-155 and downregulate the same set of targets (5).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: H Erpesvirus Saimiri (Hvs) Is a T-lymphotropic Gammaherpesvimentioning

confidence: 99%

Herpesvirus saimiri MicroRNAs Preferentially Target Host Cell Cycle Regulators

Guo

Oei

Steitz

2015

Self Cite

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