| First Author | Kawai Y | Year | 2014 |
| Journal | Immunol Cell Biol | Volume | 92 |
| Issue | 6 | Pages | 527-34 |
| PubMed ID | 24638062 | Mgi Jnum | J:297527 |
| Mgi Id | MGI:6478861 | Doi | 10.1038/icb.2014.18 |
| Citation | Kawai Y, et al. (2014) LAPTM5 promotes lysosomal degradation of intracellular CD3zeta but not of cell surface CD3zeta. Immunol Cell Biol 92(6):527-34 |
| abstractText | The lysosomal protein LAPTM5 has been shown to negatively regulate cell surface T cell receptor (TCR) expression and T-cell activation by promoting CD3zeta degradation in lysosomes, but the mechanism remains largely unknown. Here we show that LAPTM5 promotes lysosomal translocation of intracellular CD3zeta but not of the cell surface CD3zeta associated with the mature TCR complex. Kinetic analysis of the subcellular localization of the newly synthesized CD3zeta suggests that LAPTM5 targets CD3zeta in the Golgi apparatus and promotes its lysosomal translocation. Consistently, a Golgi-localizing mutant CD3zeta can be transported to and degraded in the lysosome by LAPTM5. A CD3zeta 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 CD3zeta, further suggesting that TCR signaling-triggered tyrosine phosphorylation of CD3zeta 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 CD3zeta 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 CD3zeta can be degraded by two pathways: SLAP/c-Cbl, which targets internalized cell surface CD3zeta dependent on TCR signaling, and LAPTM5, which targets intracellular CD3zeta independent of TCR signaling. |
