614097.fig.002
Figure 2: The role of CYLD in canonical and noncanonical NF-κB pathway. In the canonical NF-κB pathway, NF-κB dimmers such as p65/p50 are maintained in the cytoplasm by interaction with an IκBα protein. The binding of a ligand to a cell-surface receptor activates TAK1 which in turn activates an IKK complex, containing-α, -β, and NEMO, which is responsible for phosphorylation of IKK-β. IKK-β then phosphorylates IκB-α, leading to K48-ubiquitination and degradation of this protein. p65/p50 then freely enters the nucleus to turn on target genes. The noncanonical pathway is largely for the activation of p100/RelB complexes and differs from the classical pathway in that only certain receptor signals, activate this pathway and it proceeds through an IKK complex that contains two IKK-α subunits but not NEMO. In the noncanonical NF-κB pathway, receptor binding leads to activation of the NF-κB-inducing kinase NIK, which phosphorylates and activates an IKK-α complex that in turn phosphorylates IκB domain of p100, leading to its partial proteolysis and liberation of the p52/RelB complex. CYLD blocks canonical NF-κB pathway by the removal of Lys-63 ubiquitinated chains from activated TRAFs, RIP, NEMO, and BCL3.