Canonical NF-κB signalling and negative regulators. Ligand engagement of specific membrane receptors such as TNFR1, CD40, RANK, and TLR4 trigger the recruitment of specific adaptor proteins (TNF receptor 1-associated death domain protein (TRADD), MyD88, MAL, TIR domain-containing adaptor-inducing IFNβ (TRIF)), kinases (RIP1, IRAK1, IRAK4), and ubiquitin ligases (TRAF2, TRAF6, cIAP1, cIAP2) to the receptor. K63-linked polyubiquitination of TRAFs, RIP1 and IRAK1, is recognised by NEMO and TAB proteins, resulting in the recruitment and activation of respectively IKK2 and TAK1. TAK1 then phosphorylates and activates IKK2, which in turn phosphorylates IκBα, triggering its K48-linked ubiquitination and proteasomal degradation. This allows NF-κB (here shown as a heterodimer of p65 and p50) to translocate to the nucleus and promote target gene expression. TRAF1, which has no ubiquitin ligase activity, can negatively regulate NF-κB activation, most probably by competing with other TRAFs. A20 and CYLD are deubiquitinating enzymes that control NF-κB activation by targeting specific signalling proteins including RIP1 and TRAF6, to which they are recruited using specific ubiquitin-binding adaptor proteins such as ABIN-1 and p62. miR-146 is thought to negatively regulate TLR signalling by inhibiting expression of IRAK1 and TRAF6. Finally, TLR signalling can also be inhibited by the transmembrane protein SIGIRR, which has been proposed to compete with TLR4 for binding to IRAK1 and TRAF6. The expression of many of these negative regulatory molecules is NF-κB dependent, implicating them in the negative feedback regulation of NF-κB activation. ABIN, A20-binding inhibitor of NF-κB; cIAP, cellular inhibitor of apoptosis; CYLD, cylindromatosis; IKK, IκB kinase; IκB, inhibitor of NF-κB; IRAK, IL-1R-associated kinase; MyD88, myeloid differentiation primary response gene 88; NEMO, NF-κB essential modulator; NF, nuclear factor; RANK, receptor activator of NF-κB; RIP1, receptor interacting protein 1; SIGIRR, single-immunoglobulinIL-1 receptor-related; TIR, Toll-like receptor/IL-1R; TRAF, TNF receptor-associated factor; TLR, Toll-like receptor; TNF, tumour necrosis factor.
van Loo and Beyaert Arthritis Research & Therapy 2011 13:221 doi:10.1186/ar3324