Figure 4.

Ubiquitin regulation of T cell activation. TCR signaling is initiated by antigen/MHC-stimulated colocalization of the TCR complex with T cell coreceptor, CD4 or CD8, which allows the CD4/CD8-associated protein tyrosine kinase Lck to phosphorylate the signaling chains of TCR. Phosphorylated TCRζ chains recruit and activate the protein tyrosine kinase Zap70, which in turn phosphorylates LAT and SLP-76, triggering the recruitment and activation of key signaling components, such as PLCγ1. PLCγ1 hydrolyzes the membrane lipid PIP2 to generate second messengers, DAG and IP3, which in turn mediate activation of PKCθ, Ras, and calcium pathways, leading to activation of NF-κB, AP1, and NFAT. K63-linked ubiquitination is crucial for activation of NF-κB and AP1 pathways by the intermediate signaling complex, composed of CARMA1, BCL10, and MALT1. This complex associates with an E3 and the E2 dimer Ubc13/Uev1a to conjugate K63-linked ubiquitin chains to BCL10, thereby promoting the recruitment and activation of TAK1 and IKK. Several E3 ubiquitin ligases, including Cbl-b, c-Cbl, GRAIL, and ITCH, negatively regulate TCR-proximal signaling by mediating ubiquitin-dependent degradation of major signaling components. Some E3 ligases, likely including Nrdp1 and c-Cbl, conjugate nondegradative ubiquitin chains, including K33-linked chains, to Zap70, which facilitates the recruitment of protein tyrosine phosphatases Sts1 and Sts2 to dephosphorylate and inhibit Zap70. Peli1 and MDM2 are E3s that mediate ubiquitin-dependent degradation of activated transcription factors, c-Rel and NFATc2, respectively.