Figure 2.

Known roles of E3 ligase and DUBs in TCR signaling. Upon engagement of the TCR with peptide-MHC, several E3 ligases act to limit the strength of TCR signaling. GRAIL, CBL-B, and Itch are active in limiting proximal TCR signaling, and therefore enforcing T cell tolerance. Additional E3 ligases are activated with engagement of co-stimulatory molecules, and these E3s can promote activation of a T cell receiving signals through both the TCR and CD28 (Nedd4, WWP2), or limit signaling downstream of CD28 (TRIM27). Further downstream, activation of NF-κB is dependent on K63 chain formation on a variety of scaffolding proteins, while activity of the AP-1 complex and nuclear localization of NFAT can be inhibited directly by E3 ligase activity or by repression further upstream.