LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ

Yohei Kawai, Rika Ouchida, Sho Yamasaki, Leonard Dragone, Takeshi Tsubata, Ji Yang Wang

    Research output: Contribution to journalArticle

    6 Citations (Scopus)

    Abstract

    The lysosomal protein LAPTM5 has been shown to negatively regulate cell surface T cell receptor (TCR) expression and T-cell activation by promoting CD3ζ degradation in lysosomes, but the mechanism remains largely unknown. Here we show that LAPTM5 promotes lysosomal translocation of intracellular CD3ζ but not of the cell surface CD3ζ associated with the mature TCR complex. Kinetic analysis of the subcellular localization of the newly synthesized CD3ζ suggests that LAPTM5 targets CD3ζ in the Golgi apparatus and promotes its lysosomal translocation. Consistently, a Golgi-localizing mutant CD3ζ can be transported to and degraded in the lysosome by LAPTM5. A CD3ζ YF mutant in which all six tyrosine residues in the immunoreceptor tyrosine-based activation motif are mutated to phenylalanines is degraded as efficiently as is wild type CD3ζ, further suggesting that TCR signaling-triggered tyrosine phosphorylation of CD3ζ is dispensable for LAPTM5-mediated degradation. Previously, Src-like adapter protein (SLAP) and E3 ubiquitin ligase c-Cbl have been shown to mediate the ubiquitination of CD3ζ in the internalized TCR complex and its subsequent lysosomal degradation. We show that LAPTM5 and SLAP/c-Cbl function in distinct genetic pathways to negatively regulate TCR expression. Collectively, these results suggest that CD3ζ can be degraded by two pathways: SLAP/c-Cbl, which targets internalized cell surface CD3ζ dependent on TCR signaling, and LAPTM5, which targets intracellular CD3ζ independent of TCR signaling.

    Original languageEnglish
    Pages (from-to)527-534
    Number of pages8
    JournalImmunology and Cell Biology
    Volume92
    Issue number6
    DOIs
    Publication statusPublished - Jul 2014

    Fingerprint

    T-Cell Antigen Receptor
    Proto-Oncogene Proteins c-cbl
    Lysosomes
    Tyrosine
    Immunoreceptor Tyrosine-Based Activation Motif
    Ubiquitin-Protein Ligases
    Ubiquitination
    Golgi Apparatus
    Phenylalanine
    Phosphorylation
    T-Lymphocytes

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology
    • Cell Biology

    Cite this

    Kawai, Y., Ouchida, R., Yamasaki, S., Dragone, L., Tsubata, T., & Wang, J. Y. (2014). LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ. Immunology and Cell Biology, 92(6), 527-534. https://doi.org/10.1038/icb.2014.18

    LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ. / Kawai, Yohei; Ouchida, Rika; Yamasaki, Sho; Dragone, Leonard; Tsubata, Takeshi; Wang, Ji Yang.

    In: Immunology and Cell Biology, Vol. 92, No. 6, 07.2014, p. 527-534.

    Research output: Contribution to journalArticle

    Kawai, Y, Ouchida, R, Yamasaki, S, Dragone, L, Tsubata, T & Wang, JY 2014, 'LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ', Immunology and Cell Biology, vol. 92, no. 6, pp. 527-534. https://doi.org/10.1038/icb.2014.18
    Kawai, Yohei ; Ouchida, Rika ; Yamasaki, Sho ; Dragone, Leonard ; Tsubata, Takeshi ; Wang, Ji Yang. / LAPTM5 promotes lysosomal degradation of intracellular CD3ζ but not of cell surface CD3ζ. In: Immunology and Cell Biology. 2014 ; Vol. 92, No. 6. pp. 527-534.
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