Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance?

Figure 2

Regulation of NOD signalling by the ubiquitin-proteasome system. (a) NOD1 receptors recognize iE-DAP while NOD2 main ligand is muramyl dipeptide (MDP). (b) Similarly to NOD1, NOD2 receptors oligomerize upon ligand binding. This triggers the recruitment of RIPK2 to this complex and cIAP- and XIAP-mediated K63-ubiquitination of RIPK2. This allows the recruitment of TAK1/TAB2/TAB3 complex and LUBAC, which can also mediate the linear ubiquitination of RIPK2. TAK1 then phosphorylates IKKβ, which in turn phosphorylates IκB and subsequently undergoes ubiquitination and proteasomal degradation. This frees NF-κB (p50/p65) to translocate to the nucleus and initiate transcription. Deubiquitinases A20 and OTULIN are negative regulators of these events by deubiquitinating K63 and M1 poly-Ub chains, respectively.

(a)

(b)