A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKɛ

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Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs (pre-miRNAs). Current studies have shown that these miRNAs are involved in regulation of viral and host gene expression, implicating a role in the maintenance of viral latency and suppression of antiviral innate immunity. However, the functions of these miRNAs remain largely unknown. On the basis of the sequence homology between oncogenic miR-155 and KSHV-encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate transforming growth factor ␤ (TGF-␤) signaling, facilitating viral infection and tumorigenesis. In the present study, we demonstrated that ectopic expression of miR-K12-11 in Ramos, a TGF-␤-sensitive cell line, downregulated TGF-␤ signaling and facilitated cell proliferation upon TGF-␤ treatment by directly targeting SMAD5, an important mediator in TGF-␤ signaling. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a de novo KSHV infection system or latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 by a specific sponge inhibitor restored the expression of SMAD5 in both de novo-infected and latently infected cells. Finally, we found that restoration of SMAD5, in addition to the TGF-␤ type II receptor, which was epigenetically silenced by the latent viral protein latencyassociated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-␤ signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 downregulates TGF-␤ signaling and suggest that viral miRNAs and proteins may exert a dichotomy regulation in virus-induced oncogenesis by targeting the same signaling pathway.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5

Liu

Sun

Lin

et al. 2012

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“…Dysregulation of miRNA-mediated posttranscriptional regulatory activity appears to critically influence the "latent-to-lytic" switch in the KSHV life cycle and contribute to KS progression, either through direct targeting of the viral switch protein RTA (66,67) or via indirect mechanisms, including targeting host factors such as IB␣, nuclear factor I/B (NFIB), retinoblastoma-like 2 (Rbl2), Bcl-2 associated factor 1 (BCLAF1), and IKK⑀ (43,(68)(69)(70)(71). For example, we have previously shown that soluble and ectopic expression of HIV-1-encoded Nef protein could suppress the expression of KSHV lytic proteins and the production of viral particles through regulation of cellular miR-1258, which directly targets the 3=UTR of KSHV RTA (26).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling

Yan

Shen

Qin

et al. 2016

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The high incidence of AIDS-KS has been ascribed to the interaction of KSHV and HIV-1. We have previously shown that HIV-1-secreted proteins Tat and Nef regulate the KSHV life cycle and synergize with KSHV oncogenes to promote angiogenesis and tumorigenesis. Here, we examined the regulation of KSHV latency by HIV-1 viral protein R (Vpr). We found that soluble Vpr inhibits the expression of KSHV lytic transcripts and proteins, as well as viral particle production by activating NF-B signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identi- Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the causative agent of Kaposi's sarcoma (KS). AIDS-associated Kaposi's sarcoma (AIDS-KS) remains a clinical challenge in sub-Saharan Africa and the United States, including a subset of AIDS patients receiving highly active antiretroviral therapy (HAART) (1-4). KSHV infection is also linked to two B-cell lymphoproliferative disorders associated with AIDS, including primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease (MCD) (5, 6).KSHV displays two distinct replication phases: a latent phase and a productive lytic phase. Following acute infection, KSHV in general establishes lifetime persistence in the infected individuals. During the latent phase, only a limited number of viral genes are expressed, which serve to maintain the persistence of the viral genome, restrict host immune responses, and enhance cell survival. KSHV latently infected cells can be reactivated into lytic replication by several intracellular or extracellular stimuli, such as hypoxia, oxidative stress, and certain cytokines (7-10). Activation of viral lytic replication results in the expression of viral lytic genes and the production of infectious virions (11). Both latent and lytic replication phases are crucial for the long-term persistence of KSHV in the host, and their gene products play critical roles in the pathogenesis of KSHV-associated disease.As is true of infection with other human oncogenic viruses, KSHV infection alone is not sufficient to cause KSHV-associated malignancy (1, 12). Previously, we and others demonstrated that other cofactors, such as human herpesvirus 6 (HHV-6), herpes simplex virus 1 (HSV-1), human immunodeficiency virus type 1

“…One major clue to the potential functions of the KSHV miRNAs is the identification of two of the KSHV miRNAs as viral analogs of the cellular miRNAs miR-155 and miR-142-3p (12,14,15). Several additional interactions and functions of the KSHV miRNAs have been identified (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35); however, the overall impact these miRNAs have on host gene expression and their phenotypic consequences remain largely unknown.…”

mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of Cellular miR-23

Manzano

Shamulailatpam

Raja

et al. 2013

Kaposi's sarcoma-associated herpesvirus (KSHV) expresses ϳ20 viral microRNAs (miRNAs) in latently infected cells. We have previously shown that two of these miRNAs function as mimics of the cellular miRNAs miR-155 and miR-142-3p. Two additional KSHV miRNAs, miR-K3؉1 and miR-K3, share perfect and offset 5= homology with cellular miR-23, respectively. Here, we report a single nucleotide polymorphism that causes miR-K3؉1 expression in a subset of KSHV-infected primary effusion lymphoma cell lines as a consequence of altered processing of the primary transcript by the Microprocessor complex. We confirm that miR-K3؉1 regulates miR-23 targets, which is expected because these miRNAs share the entire seed region (nucleotides 2 to 8). Surprisingly, we found that miR-K3 also regulates miR-23 targets, despite offset seed sequences. In addition, the offset homology of miR-K3 to miR-23 likely allows this viral miRNA to expand its target repertoire beyond the targets of miR-23. Because miR-23 is highly expressed in endothelial cells but expressed at only low levels in B cells, we hypothesize that miR-K3 may function to introduce miR-23-like activities into KSHV-infected B cells. Together, our data demonstrate that KSHV has evolved at least three distinct viral miRNAs to tap into evolutionarily conserved cellular miRNA-regulatory networks. Furthermore, our data allow fundamental insights into the generation and functional impact of miRNA 5= end variation.