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  • Grb2-mediated recruitment of USP9X to LAT enhances themis stability following thymic selection

    Author(s)
    Garreau, Anne
    Blaize, Gaetan
    Argenty, Jeremy
    Rouquie, Nelly
    Tourdes, Audrey
    Wood, Stephen A
    Saoudi, Abdelhadi
    Lesourne, Renaud
    Griffith University Author(s)
    Wood, Stephen A.
    Year published
    2017
    Metadata
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    Abstract
    Themis is a new component of the TCR signaling machinery that plays a critical role during T cell development. The positive selection of immature CD4+CD8+ double-positive thymocytes and their commitment to the CD4+CD8− single-positive stage are impaired in Themis−/− mice, suggesting that Themis might be important to sustain TCR signals during these key developmental processes. However, the analysis of Themis mRNA levels revealed that Themis gene expression is rapidly extinguished during positive selection. We show in this article that Themis protein expression is increased in double-positive thymocytes undergoing positive ...
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    Themis is a new component of the TCR signaling machinery that plays a critical role during T cell development. The positive selection of immature CD4+CD8+ double-positive thymocytes and their commitment to the CD4+CD8− single-positive stage are impaired in Themis−/− mice, suggesting that Themis might be important to sustain TCR signals during these key developmental processes. However, the analysis of Themis mRNA levels revealed that Themis gene expression is rapidly extinguished during positive selection. We show in this article that Themis protein expression is increased in double-positive thymocytes undergoing positive selection and is sustained in immature single-positive thymocytes, despite the strong decrease in Themis mRNA levels in these subsets. We found that Themis stability is controlled by the ubiquitin-specific protease USP9X, which removes ubiquitin K48-linked chains on Themis following TCR engagement. Biochemical analyses indicate that USP9X binds directly to the N-terminal CABIT domain of Themis and indirectly to the adaptor protein Grb2, with the latter interaction enabling recruitment of Themis/USP9X complexes to LAT, thereby sustaining Themis expression following positive selection. Together, these data suggest that TCR-mediated signals enhance Themis stability upon T cell development and identify USP9X as a key regulator of Themis protein turnover.
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    Journal Title
    Journal of Immunology
    Volume
    199
    DOI
    https://doi.org/10.4049/jimmunol.1700566
    Copyright Statement
    Self-archiving of the author-manuscript version is not yet supported by this journal. Please refer to the journal link for access to the definitive, published version or contact the author[s] for more information.
    Subject
    Immunology
    Immunology not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/355159
    Collection
    • Journal articles

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