Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70.
Triggering of the T cell antigen receptor (TCR).CD3 complex induces its ubiquitination. However, the molecular events that lead to ubiquitin conjugation to these cell surface molecules have not been defined. Here we report that Cbl, a RING-type E3 ubiquitin-protein ligase, promotes ubiquitination of TCR zeta chain, which requires its functional variant Src homology 2 domain and an intact RING finger. The tyrosine kinase Zap-70, which binds to both TCR zeta and Cbl, plays an adaptor role in these events. Mutations in TCR zeta, Zap-70, or Cbl that disrupt the interaction between TCR zeta and Zap-70 or between Zap-70 and Cbl reduce ubiquitination of TCR zeta. Our results suggest a novel mechanism by which Cbl negatively regulates T cell development and activation by inducing ubiquitination of the TCR.CD3 components.
Wang
H Y
HY
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Altman
Y
Y
Fang
D
D
Elly
C
C
Dai
Y
Y
Shao
Y
Y
Liu
Y C
YC
D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D050722:Oncogene Protein v-cbl; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D008565:Membrane Proteins; D050722:Oncogene Protein v-cbl; D011948:Receptors, Antigen, T-Cell; D015682:Retroviridae Proteins, Oncogenic; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human