MicroRNA editing facilitates immune elimination of HCMV infected cells

PLoS Pathog. 2014 Feb 27;10(2):e1003963. doi: 10.1371/journal.ppat.1003963. eCollection 2014 Feb.

Abstract

The human cytomegalovirus (HCMV) is extremely prevalent in the human population. Infection by HCMV is life threatening in immune compromised individuals and in immune competent individuals it can cause severe birth defects, developmental retardation and is even associated with tumor development. While numerous mechanisms were developed by HCMV to interfere with immune cell activity, much less is known about cellular mechanisms that operate in response to HCMV infection. Here we demonstrate that in response to HCMV infection, the expression of the short form of the RNA editing enzyme ADAR1 (ADAR1-p110) is induced. We identified the specific promoter region responsible for this induction and we show that ADAR1-p110 can edit miR-376a. Accordingly, we demonstrate that the levels of the edited-miR-376a (miR-376a(e)) increase during HCMV infection. Importantly, we show that miR-376a(e) downregulates the immune modulating molecule HLA-E and that this consequently renders HCMV infected cells susceptible to elimination by NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics*
  • Blotting, Western
  • Cytomegalovirus
  • Cytomegalovirus Infections / genetics*
  • Cytomegalovirus Infections / immunology*
  • Humans
  • Killer Cells, Natural / immunology*
  • MicroRNAs / genetics*
  • RNA Editing / genetics*
  • RNA-Binding Proteins

Substances

  • MicroRNAs
  • RNA-Binding Proteins
  • ADARB1 protein, human
  • Adenosine Deaminase

Grant support

This study was supported by grants from the Israeli Science Foundation, by the advanced ERC grant, by the ICRF professorship grant, by the I-CORE, and by the GIF grant (all to OM). NS, EG, and OM are supported by the I-CORE Program of the Planning and Budgeting Committee, The Israel Science Foundation (grant number 41/11). NS is supported by the Chief Scientist Office, Ministry of Health, Israel; Israel Cancer Association and the Wolfson family Charitable Fund. EG was funded by the German Research Foundation (DFG) SFB 841. OM is a Crown professor of Molecular Immunology. DN is supported by the Adams fellowship program of the Israel Academy of Sciences and Humanities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.