A lysosomal protein negatively regulates surface T cell antigen receptor expression by promoting CD3 zeta-chain degradation

作者：Ouchida Rika; Yamasaki Sho; Hikida Masaki; Masuda Keiji; Kawamura Kiyoko; Wada Akihiko; Mochizuki Shigenobu; Tagawa Masatoshi; Sakamoto Akemi; Hatano Masahiko; Tokuhisa Takeshi; Koseki Haruhiko; Saito Takashi; Kurosaki Tomohiro; Wang Ji Yang^*

来源：Immunity, 2008, 29(1): 33-43.

DOI：10.1016/j.immuni.2008.04.024

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 CD3 zeta chain and promoting its degradation without affecting other CD3 proteins, CD3 epsilon, CD3 delta, or CD3 gamma. 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 CD3 zeta degradation and illustrate a unique mechanism for the control of surface TCR expression and T cell activation.

• 出版日期2008-7-18