title: A lysosomal protein negatively regulates surface T cell antigen receptor expression by promoting CD3zeta-chain degradation.
abstract: Modulation of surface T cell antigen receptor (TCR) expression is an important mechanism for the regulation of immune responses and the prevention of T cell hyperactivation and autoimmunity. The TCR is rapidly internalized after antigen stimulation and then degraded in lysosomes. However, few of the molecules involved in this process have been identified. We demonstrate that the lysosomal protein LAPTM5 negatively regulated surface TCR expression by specifically interacting with the invariant signal-transducing CD3zeta chain and promoting its degradation without affecting other CD3 proteins, CD3epsilon, CD3delta, or CD3gamma. TCR downmodulation required the polyproline-tyrosine motifs and the ubiquitin-interacting motif of LAPTM5. LAPTM5 deficiency resulted in elevated TCR expression on both CD4(+)CD8(+) thymocytes and spleen T cells after CD3 stimulation, as well as enhanced T cell responses in vitro and in vivo. These results identify a lysosomal protein important for CD3zeta degradation and illustrate a unique mechanism for the control of surface TCR expression and T cell activation.
authors.affiliation: Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Ouchida
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.forename: Keiji
authors.initials: K
authors.lastname: Masuda
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kawamura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Wada
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.forename: Ji-Yang
authors.initials: JY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D017874:Immediate-Early Proteins / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D017874:Immediate-Early Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C018589:lysosomal proteins