Cbl Promotes Ubiquitination of the T Cell Receptor ζ 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 TCRζ chain, which requires its functional variant Src homology 2 domain and an intact RING finger. The tyrosine kinase Zap-70, which binds to both TCRζ and Cbl, plays an adaptor role in these events. Mutations in TCRζ, Zap-70, or Cbl that disrupt the interaction between TCRζ and Zap-70 or between Zap-70 and Cbl reduce ubiquitination of TCRζ. Our results suggest a novel mechanism by which Cbl negatively regulates T cell development and activation by inducing ubiquitination of the TCR·CD3 components.