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The MCMV immunoevasin gp40/m152 inhibits NKG2D receptor RAE-1γ by intracellular retention and cell surface masking

View ORCID ProfileNatalia Lis, View ORCID ProfileZeynep Hein, View ORCID ProfileSwapnil S. Ghanwat, View ORCID ProfileVenkat Raman Ramnarayan, View ORCID ProfileBenedict J. Chambers, View ORCID ProfileSebastian Springer
doi: https://doi.org/10.1101/2020.11.17.386763
Natalia Lis
1Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany
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Zeynep Hein
1Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany
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Swapnil S. Ghanwat
1Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany
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Venkat Raman Ramnarayan
1Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany
2Department of Molecular Biology, Universitätsmedizin Göttingen, Göttingen, Germany
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Benedict J. Chambers
3Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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Sebastian Springer
1Department of Life Sciences and Chemistry, Jacobs University, Bremen, Germany
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  • For correspondence: s.springer@jacobs-university.de
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Abstract

NKG2D is a crucial Natural Killer (NK) cell activating receptor, and the murine cytomegalovirus (MCMV) employs multiple immunoevasins in order to avoid NKG2D-mediated activation. One of the MCMV immunoevasins, gp40 (m152), downregulates the cell surface NKG2D ligand, RAE-1γ, thus limiting NK cell activation. This study establishes the molecular mechanism by which gp40 retains RAE-1γ in the secretory pathway. Using flow cytometry and pulse chase analysis, we demonstrate that gp40 retains RAE-1γ in the early secretory pathway, and that this effect depends on the binding of gp40 to a host protein, TMED10, a member of the p24 protein family. We also show that the TMED10-based retention mechanism can be saturated, and that gp40 has a backup mechanism as it masks RAE-1γ on the cell surface, blocking the interaction with the NKG2D receptor and thus NK cell activation.

Summary statement MCMV immunoevasin gp40 inhibits the NKG2D-activating ligand RAE-1γ by intracellular retention that depends on the p24 member TMED10, and additionally by masking it at the cell surface.

  • List of Symbols and Abbreviations

    HCMV
    Human Cytomegalovirus
    MCMV
    murine cytomegalovirus
    NK cell
    natural killer cell
    Endo F1
    endoglycosidase F1
    TMED10
    transmembrane p24 trafficking protein 10
    CX1
    monoclonal anti-RAE 1γ antibody
    gp40-
    cells transfected with HA-RAE-1γ without gp40
    gp40+
    cells transfected with HA-RAE-1γ and gp40
    gp40LM
    gp40 linker mutant
    gp40WT
    gp40 wild type
    PDM
    Protein Deglycosylation Mix
    APC
    APC-conjugated secondary antibody
    RE-IP
    re-immunoprecipitation.
  • Copyright 
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    Posted November 17, 2020.
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    The MCMV immunoevasin gp40/m152 inhibits NKG2D receptor RAE-1γ by intracellular retention and cell surface masking
    Natalia Lis, Zeynep Hein, Swapnil S. Ghanwat, Venkat Raman Ramnarayan, Benedict J. Chambers, Sebastian Springer
    bioRxiv 2020.11.17.386763; doi: https://doi.org/10.1101/2020.11.17.386763
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    The MCMV immunoevasin gp40/m152 inhibits NKG2D receptor RAE-1γ by intracellular retention and cell surface masking
    Natalia Lis, Zeynep Hein, Swapnil S. Ghanwat, Venkat Raman Ramnarayan, Benedict J. Chambers, Sebastian Springer
    bioRxiv 2020.11.17.386763; doi: https://doi.org/10.1101/2020.11.17.386763

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