Negative regulation of NF-κB and its involvement in rheumatoid arthritis

Abstract

The transcription factor NF-κB plays crucial roles in the regulation of inflammation and immune responses, and inappropriate NF-κB activity has been linked with many autoimmune and inflammatory diseases, including rheumatoid arthritis. Cells employ a multilayered control system to keep NF-κB signalling in check, including a repertoire of negative feedback regulators ensuring termination of NF-κB responses. Here we will review various negative regulatory mechanisms that have evolved to control NF-κB signalling and which have been implicated in the pathogenesis of rheumatoid arthritis.

Figure 1

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.

Figure 2

Noncanonical NF-κB signalling. CD40 and RANK can activate the noncanonical NF-κB pathway that is dependent on NF-κB inducing kinase (NIK) expression levels. In unstimulated cells NIK forms a cytosolic complex with the ubiquitin ligases TRAF2, TRAF3 and cIAP1/2, which facilitates the K48-linked polyubiquitination and proteasomal degradation of NIK, keeping NIK levels low. Upon ligand binding, TRAF3 is recruited to the receptor, where TRAF2 directs nondegradative K63-linked polyubiquitination of cIAP1/2, resulting in their activation. Subsequently cIAP1/2 directs its K48-linked polyubiquitination to TRAF3, rather than NIK. As a result, TRAF3 is degraded and NIK is stabilised, resulting in increased NIK levels in the cell. NIK then phosphorylates and activates IKK1, which mediates NF-κB p100 phosphorylation. This is followed by K48-linked polyubiquitination and partial proteasomal degradation of p100 to p52, which forms a heterodimer with RelB to activate transcription. Next to TRAF3, TRAF1 has also been identified as a negative regulator of this pathway, most probably by competing with other TNF receptor-associated factors. cIAP, cellular inhibitor of apoptosis; IKK, IκB kinase; NF, nuclear factor; RANK, receptor activator of NF-κB; TRAF, TNF receptor-associated factor; TNF, tumour necrosis factor.