Although approximately 200 viral microRNAs are known, only very few share similar targets with their host's microRNAs. A notable example of this is the stress-induced ligand MICB, which is targeted by several distinct viral and cellular microRNAs. Through the investigation of the microRNA-mediated immune-evasion strategies of herpesviruses, we initially identified two new cellular microRNAs that targeted MICB and were expressed differently both in healthy tissues and during melanocyte transformation. We show that coexpression of various pairs of cellular microRNAs interfered with the downregulation of MICB, whereas the viral microRNAs optimized their targeting ability to efficiently downregulate MICB. Moreover, we demonstrate that through site proximity and possibly inhibition of translation, a human cytomegalovirus (HCMV) microRNA acts synergistically with a cellular microRNA to suppress MICB expression during HCMV infection.
Bibliographical noteFunding Information:
We thank A. Bernard (Hôpital de l’Archet, Nice, France) for monoclonal anti-CD99 (12E7); Y. Livneh, D. Davis and S. Jonjic and all members of the Mandelboim laboratory for suggestions and discussions and for critical reading of the manuscript; S. Diederichs and W. Filipowicz for discussions and suggestions; and M. Lotem and team (Hadassah Hospital) for primary melanocytes and nevi. Supported by the Israeli Science Foundation (O.M.), The Israeli Science Foundation (Morasha, to O.M.), Croatia-Israel Research (O.M.), Ministry of Science and Technology–Deutsches Krebsforschungszentrum (O.M.), The European Consortium (MRTN-CT-2005 to O.M.), Rosetrees Trust (O.M.), the Israel Cancer Association (20100003 to O.M.) and the Association for International Cancer Research (O.M.).