Date Published: February 27, 2014
Publisher: Public Library of Science
Author(s): 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, Shou-Jiang Gao.
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.
HCMV is a dsDNA herpesvirus, which is highly prevalent in the human population. It establishes its life long latency by using a diverse panel of sophisticated immune evasion strategies, and specifically by manipulating the expression of Human Leukocyte Antigen (HLA) class I molecules –. One of the fascinating examples with this regard is the viral protein UL40 that encodes a signal peptide similar in its sequence to the signal peptide of HLA class I molecules. The UL40 signal peptide is processed and loaded specifically in the groove of HLA-E and thus induces its surface expression, where it can inhibit NK cells function , .
ADAR1 encodes two isoforms: ADAR1-p110, which was until now thought to be constitutively expressed, and ADAR1-p150, which is IFN-induced. These two isoforms are located at different compartments in the cell; ADAR1-p110 is located primarily in the nucleus, and ADAR1-p150 is located mainly in the cytoplasm . It is therefore expected that each isoform will have a specific range of RNA targets, and thus different roles in different physiological conditions.