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Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D

Nature Immunology volume 9, pages 1065–1073 (2008)Cite this article

Abstract

MICA and MICB are stress-induced ligands recognized by the activating receptor NKG2D. A microRNA encoded by human cytomegalovirus downregulates MICB expression by targeting a specific site in the MICB 3′ untranslated region. As this site is conserved among different MICB alleles and a similar site exists in the MICA 3′ untranslated region, we speculated that these sites are targeted by cellular microRNAs. Here we identified microRNAs that bound to these MICA and MICB 3′ untranslated region sequences and obtained data suggesting that these microRNAs maintain expression of MICA and MICB protein under a certain threshold and facilitate acute upregulation of MICA and MICB during cellular stress. These microRNAs were overexpressed in various tumors and we demonstrate here that they aided tumor avoidance of immune recognition.

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Figure 1: Possible influence of microRNA on MICA and MICB expression.
Figure 2: Shared target sequences recognized by both viral and human microRNAs to control MICA and MICB expression.
Figure 3: Human microRNAs specifically downregulate MICA and MICB expression.
Figure 4: Human microRNAs control MICA and MICB expression in normal conditions.
Figure 5: Control of MICA and MICB expression during short-term stress responses.
Figure 6: MicroRNAs set a threshold for MICA and MICB protein expression.
Figure 7: Overexpression of relevant microRNAs confers protection from lysis by NK cells.

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Acknowledgements

We thank D. Cosman (Amgen) for the NKG2D-Ig constructs and A. Bernard (Hôpital de L'Archet) for anti-CD99. Supported by the United States–Israel Binational Science Foundation (O.M.), the Israeli Cancer Research Foundation (O.M.), the Israeli Science Foundation (O.M.), the European Consortium (MRTN-CT-2005 and LSCH-CT-2005-518178 to O.M.), the Association for International Cancer Research (O.M.) and the Israel Academy of Sciences and Humanities (Adams Fellowship to N.S.-G.).

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Authors and Affiliations

  1. Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Hadassah Medical School, Jerusalem, 91120, Israel

    Noam Stern-Ginossar, Chamutal Gur, Moshe Biton, Elad Horwitz, Moran Elboim, Noa Stanietsky & Ofer Mandelboim

  2. Clinical Virology Unit, Tel-Hashomer, Ramat Gan, 52621, Israel

    Michal Mandelboim

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Contributions

N.S.-G. designed and did the experiments; C.G. helped with mouse experiments; M.B., E.H., M.E., N.S. and M.M. provided reagents; O.M. designed the experiments and supervised the project; and N.S.-G. and O.M. analyzed the results and wrote the paper.

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Correspondence to Ofer Mandelboim.

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Stern-Ginossar, N., Gur, C., Biton, M. et al. Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol 9, 1065–1073 (2008). https://doi.org/10.1038/ni.1642

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