title: Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs during latency that are processed to yield ~25 mature microRNAs (miRNAs). We were interested in identifying cellular networks that were targeted by KSHV-miRNAs and employed network building strategies using validated KSHV miRNA targets. Here, we report the identification of a gene network centering on the transcription factor- signal transducer and activator of transcription 3 (STAT3) that is targeted by KSHV miRNAs. KSHV miRNAs suppressed STAT3 and STAT5 activation and inhibited STAT3-dependent reporter activation upon IL6-treatment. KSHV miRNAs also repressed the induction of antiviral interferon-stimulated genes upon IFNα- treatment. Finally, we observed increased lytic reactivation of KSHV from latently infected cells upon STAT3 repression with siRNAs or a small molecule inhibitor. Our data suggest that treatment of infected cells with a STAT3 inhibitor and a viral replication inhibitor, ganciclovir, represents a possible strategy to eliminate latently infected cells without increasing virion production. Together, we show that KSHV miRNAs suppress a network of targets associated with STAT3, deregulate cytokine-mediated gene activation, suppress an interferon response, and influence the transition into the lytic phase of viral replication.
authors.affiliation: HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Dhivya
authors.initials: D
authors.lastname: Ramalingam
authors.affiliation: HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ziegelbauer
mesh_terms: D020413:3' Untranslated Regions; D000070416:Antagomirs; D001483:Base Sequence; D053263:Gene Regulatory Networks; D005822:Genetic Vectors; D019288:Herpesvirus 8, Human / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D007372:Interferons / Q000378:metabolism*; D015850:Interleukin-6 / Q000494:pharmacology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
chemical_list: D020413:3' Untranslated Regions; D000070416:Antagomirs; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D035683:MicroRNAs; D034741:RNA, Small Interfering; D017467:Receptors, Erythropoietin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D007372:Interferons