Cellular microRNAs 498 and 320d regulate herpes simplex virus 1 induction of Kaposi's sarcoma-associated herpesvirus lytic replication by targeting RTA

PLoS One. 2013;8(2):e55832. doi: 10.1371/journal.pone.0055832. Epub 2013 Feb 13.

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) infection was necessary but not sufficient for KS development without other cofactors. We have previously reported that herpes simplex virus (HSV)-1 was an important cofactor that reactivated KSHV from latency by inducing the expression of KSHV replication and transcription activator (RTA), the lytic switch protein. Here, we further investigated the possible cellular microRNAs (miRNAs) involved in regulation of RTA during HSV-1-induced KSHV replication. The differential profiles of miRNAs expression between Mock- and HSV-1-infected body cavity-based lymphoma (BCBL-1) cells were identified by miRNA microarray analysis. Bioinformatics and luciferase reporter analyses showed that two of the HSV-1-downregulated cellular miRNAs, miR-498 and miR-320d, directly targeted the 3' untranslated region (UTR) of KSHV RTA. As a result, overexpression of these two miRNAs significantly inhibited HSV-1-induced KSHV replication, whereas repression of these miRNAs with specific suppressors enhanced HSV-1-mediated KSHV replication. In addition, miR-498 or miR-320d alone, without HSV-1 infection, regulated KSHV replication in BCBL-1 cells. Finally, bioinformatics Gene Ontology (GO) analysis indicated that targets of HSV-1-regulated miRNAs were enriched for proteins, whose roles were involved in protein binding, enzyme activity, biological regulation, and several potential signaling pathways including transforming growth factor (TGF)-β were likely to participate in HSV-1-induced KSHV replication. Collectively, these novel findings demonstrated that host-encoded miR-498 and miR-320d regulated HSV-1 induction of KSHV lytic replication by targeting RTA, which provided further insights into the molecular mechanisms controlling KSHV lytic replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Cell Line, Tumor
  • Gene Expression Regulation, Viral
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / metabolism*
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / metabolism*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Signal Transduction / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Virus Activation / genetics*
  • Virus Latency / genetics

Substances

  • 3' Untranslated Regions
  • MIRN320 microRNA, human
  • MIRN498 microRNA, human
  • MicroRNAs
  • ORF 50 transactivator
  • Trans-Activators

Grant support

This work was supported by grants from the National Basic Research Program of China (973 Program) (2011CB504803) (http://www.973.gov.cn/English/Index.aspx), National Natural Science Foundation of China (grants 81171552, 81210108028, and 30972619 to CL, 30900064 to DQ, 31270199 to ZB, 81071345 to YZ, and 81272831 to NF) (http://www.nsfc.gov.cn/Portal0/default152.htm), Natural Science Foundation of Ministry of Education of Jiangsu Province (great project 10KJA310032 to CL) (http://www.jsjyt.gov.cn/), Research Fund for the Doctoral Program of Higher Education of China (New Teacher Fund, grant 20093234120004 to DQ) (http://www.cutech.edu.cn/cn/index.htm), Natural Science Foundation of Jiangsu Province (BK2010577 to NF) (http://www.jsnsf.gov.cn/Index.aspx), and Jiangsu Province’s Outstanding Medical Academic Leader Program (RC201178 to NF) (http://www.jswst.gov.cn/gb/jsswst/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.