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Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1

Nature Immunology volume 12, pages 984–991 (2011)Cite this article

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Abstract

Major histocompatibility complex (MHC) class I molecules present peptides on the cell surface to CD8+ T cells, which is critical for the killing of virus-infected or transformed cells. Precursors of MHC class I–presented peptides are trimmed to mature epitopes by the aminopeptidase ERAP1. The US2–US11 genomic region of human cytomegalovirus (HCMV) is dispensable for viral replication and encodes three microRNAs (miRNAs). We show here that HCMV miR-US4-1 specifically downregulated ERAP1 expression during viral infection. Accordingly, the trimming of HCMV-derived peptides was inhibited, which led to less susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes (CTLs). Our findings identify a previously unknown viral miRNA–based CTL-evasion mechanism that targets a key step in the MHC class I antigen-processing pathway.

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Figure 1: Expression of HCMV miR-US4-1 results in less ERAP1b mRNA and protein but not less ERAP1a mRNA or protein.
Figure 2: HCMV miR-US4-1 targets the 3′ UTR of ERAP1b and physically binds to ERAP1b mRNA in the RISC.
Figure 3: Downregulation of ERAP1 in HCMV-infected HFF cells.
Figure 4: HCMV miR-US4 inhibits the trimming of OVA8 peptide from OVA precursor peptide by ERAP1.
Figure 5: HCMV miR-US4-1 inhibits the generation of HCMV-derived antigenic peptides and CD8+ CTL responses.

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Acknowledgements

We thank M. Tsujimoto (RIKEN, Wako) for recombinant human ERAP1 cDNA and polyclonal antibody to ERAP1; P. van Endert and L. Saveanu (Institut National de la Santé et de la Recherché Médicale, Paris) for monoclonal antibody 6H9 to ERAP1; I. York (Michigan State University) and K. Rock (University of Massachusetts Medical School) for pUG1-based vectors and technical help; N. Shastri (University of California, Berkeley) for the B3Z T cell hybridoma; T. Shenk (Princeton University) for pAD/Cre BAC; and C.-Y. Kang and T.-K. Kim for technical help. Supported by the Creative Research Initiatives Program of the Ministry of Science and Technology and the Korea Science and Engineering Foundation (K.A.), the Brain Korea 21 project of the Ministry of Education, Science and Technology of the Republic of Korea (S.K., S.L. and D.K.) and the US National Institutes of Health (CA18029 and AI053193 to S.R.R.).

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Authors and Affiliations

  1. Department of Biological Sciences, National Creative Research Initiative Center for Antigen Presentation, Seoul National University, Seoul, Republic of Korea

    Sungchul Kim, Sanghyun Lee, Youngkyun Kim, Donghyun Kim & Kwangseog Ahn

  2. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA

    Jinwook Shin

  3. Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research Demokritos, Athens, Greece

    Irini Evnouchidou & Efstratios Stratikos

  4. Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea

    Young-Kook Kim & V Narry Kim

  5. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Seoul, Republic of Korea

    Young-Eui Kim & Jin-Hyun Ahn

  6. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    Stanley R Riddell

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Contributions

S.K., D.K., Y.-K.K. and V.N.K. designed and did biochemical and cell biological experiments; J.S. and Y.K. did microarray experiments; S.L., Y.-E.K. and J.-H.A. generated HCMV mutants; I.E. and E.S. did in vitro ERAP1 trimming assays; S.R.R. cloned the HCMV-specific CTLs; and S.K. and K.A. designed the overall study and wrote the paper.

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Correspondence to Kwangseog Ahn.

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Kim, S., Lee, S., Shin, J. et al. Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol 12, 984–991 (2011). https://doi.org/10.1038/ni.2097

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