Figure 4

Schematic demonstrating the role of Pellino 3 in inflammation. (A) Recognition of bacterial products by nucleotide-binding oligomerization domain-containing protein 2 (NOD2), results in NOD2 oligomerization and recruitment of receptor-interacting-serine/threonine-protein kinase 2 (RIP2). This complex then recruits Pellino 3 which ubiquitinylates (Ub) RIP2 leading to the recruitment of TGFβ-activated kinase 1 (TAK1) and the IKK complex. This facilitates activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways culminating in the induction of inflammatory cytokines and chemokines. (B) Ligand interactions with Toll-like receptor 3 (TLR3) results in the recruitment of TIR domain-containing adaptor protein-inducing IFNβ (TRIF) which initiates a signal cascade that results in the phosphorylation and ubiquitylation of interferon-regulatory factor 3 (IRF3) and IRF7 via TANK-binding kinase 1 (TBK1)–IκB kinase-ε (IKKε)and TNF receptor-associated factor 6 (TRAF6) respectively. Nuclear translocation of IRF3 and IRF7 induce the expression of type I IFNs. Additionally the TBK1–IKKε–IRF3 pathway also induces the Pellino 3 expression resulting in ubiquitylation of TRAF6 and inhibition of type I IFN expression.