title: EBV microRNA BART 18-5p targets MAP3K2 to facilitate persistence in vivo by inhibiting viral replication in B cells.
abstract: EBV is an oncogenic human herpesvirus that has the ability to infect and transform B cells latently in vitro. However, the virus also establishes a lifetime, benign, persistent latent infection in resting memory B cells in vivo, where the virus is quiescent (i.e., expresses none of the known latent proteins). The virus encodes ∼40 micro-RNAs (miRNAs), most of which are transcribed from the BamH1 fragment A rightward transcript (BART) region of the virus. We have shown previously that a subset of these miRNAs is present at high copy numbers in latently infected memory B cells in vivo, suggesting a role in maintaining latency. Here, we describe the role of one of these miRNAs, BART 18-5p. We show that it targets the 3'UTR of the mRNA, encoding the important cellular signaling molecule MAP kinase kinase kinase 2 (MAP3K2), at exactly the same site as the oncogenic cellular miRNA mir-26a-5p. To our knowledge, this is the first report of a virus encoding a miRNA that suppresses a target in the MAP kinase signaling cascade, a central signal transduction pathway that governs a broad spectrum of biological processes. We further show that MAP3K2 is an intermediary in the signaling pathways that initiate lytic viral replication. Thus, 18-5p expression in latently infected B cells has the effect of blocking viral replication. We propose that the role of 18-5p is to maintain latency by reducing the risk of fortuitous reactivation of the virus in latently infected memory B cells.
authors.affiliation: Department of Pathology, Tufts University School of Medicine, Boston, MA 02111.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Pathology, Tufts University School of Medicine, Boston, MA 02111 david.thorley-lawson@tufts.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Thorley-Lawson
mesh_terms: D020413:3' Untranslated Regions; D002461:Cell Line, Transformed; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D012367:RNA, Viral; D048730:MAP Kinase Kinase Kinase 2; D020930:MAP Kinase Kinase Kinases; C482618:MAP3K2 protein, human
keywords: EBV miRNA; MAPK pathway; viral reactivation