Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Figure 1

Regulation of TLR4 signalling by the ubiquitin-proteasome system. In MyD88-dependent signalling, TRAF6 and cIAP1/2s mediate K48 polyubiquitination and consequent degradation of TRAF3 by the proteasome. TRAF6 synthesizes K63 poly-Ub chains, which act as a scaffold for TAK1 and IKK complexes, TAB2/3 and NEMO. This occurs with the help of LUBAC, which leads to the linear ubiquitination of NEMO required for the recruitment of the IKK complex (IKKα and IKKβ). As a result, TAK1 phosphorylates IKKβ, which in turn phosphorylates IκB and subsequently undergoes ubiquitination and proteasomal degradation. This event frees NF-κB (p50/p65) to translocate to the nucleus and initiate transcription. Several DUBs (in blue) remove ubiquitin chains from TRAF6, NEMO, or NF-κB, negatively regulating this signalling pathway. USP7 can also prevent NF-κB degradation hence positively regulating transcription. MyD88-independent signalling occurs through TRAM/TRIF. In this case K63 poly-Ub chains are added to TRAF3, which consequently recruits the TBK1/IKKε kinase complex. This phosphorylates IRF3 allowing nuclear translocation and initiation of transcription. The DUB MYSM1 can deubiquitinate TRAF3, controlling the extent of this signalling.