MicroRNA editing facilitates immune elimination of HCMV infected cells

Daphna Nachmani; Albert Zimmermann; Esther Oiknine Djian; Yiska Weisblum; Yoav Livneh; Vu Thuy Khanh Le; Eithan Galun; Vaclav Horejsi; Ofer Isakov; Noam Shomron; Dana G Wolf; Hartmut Hengel; Ofer Mandelboim

doi:10.1371/journal.ppat.1003963

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.

Authors

Affiliations

¹ The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
² Department of Virology, Institute for Medical Microbiology and Hygiene, Albert-Ludwigs-Universitat, Freiburg, Germany.
³ Virology Unit, Hadassah Hospital, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
⁴ Department of Neurobiology, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.
⁵ Institute for Virology of the University Hospital Essen, University Duisburg-Essen, Essen, Germany.
⁶ Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
⁷ Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
⁸ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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

Grants and funding

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.