Table 2.
Inhibitors of TNFR signalling
| Inhibitor | Description | Mechanisms |
|---|---|---|
| Regulators of ubiquitination | ||
| A20 | • OTU-domain DUB • Inducible by TNF, via a GSK-3β-dependent mechanism76 • Interacts with partners, such as Itch, TAX1BP1, RNF11, protein Ymer and ABINs, to form ubiquitin-editing complexes36,131-133 • Polymorphisms or mutations of the gene encoding A20 (TNFAIP3) are associated with inflammatory diseases such as RA, SLE, psoriasis, and IBD134 |
• DUB: cleaves Lys63-linked ubiquitin chains from RIPK1 and NEMO135 • E3 ubiquitin ligase: conjugates Lys48-linked ubiquitin chains to RIPK1, UbcH5c and Ubc13, inducing their proteasomal degradation135 • Antagonistic ubiquitin binder: antagonizes the binding of LUBAC, NEMO, and E2 ubiquitin-conjugating enzymes32,33 • Targets signalling effectors for lysosomal degradation37 |
| Cezanne | • OTU-domain DUB • Inducible by TNF |
DUB: cleaves primarily Lys11-linked ubiquitin chains from targets such as RIPK1 (REF. 136) |
| Ubiquitin thioesterase otulin | • OTU-domain DUB • Not inducible by TNF • Has high specificity for inhibiting events related to linear ubiquitination |
• DUB: cleaves linear ubiquitin chains from RIPK1 and NEMO, destabilizing complex I137 • Antagonistic ubiquitin binder: antagonizes the binding of NEMO to Met1-linked ubiquitin chains34 • Regulator: interacts directly with HOIP, regulating its ligase-activity138,139 |
| Ubiquitin carboxyl-terminal hydrolase CYLD | • USP-family DUB • Interacts with partners, such as Itch, p62, HOIP and optineurin35 • Individuals with mutations of CYLD are predisposed to cylindromatosis140 |
Cleaves primarily Lys63-linked ubiquitin chains and secondarily linear chains from NEMO, TRAF2 and TAK1 (REF. 141) |
| USP4 | USP-family DUB | • Cleaves Lys63-linked ubiquitin chains from TRAF2, RIPK1 and TAK1 (REF. 142) |
| USP11 | USP-family DUB | • Cleaves Lys48-linked ubiquitin chains from IκBs, preventing their proteasomal degradation and the release of NFκB28 |
| USP15 | USP-family DUB | • Cleaves Lys48-linked ubiquitin chains from IκBs, preventing their proteasomal degradation and the release of NFκB28 |
| USP21 | USP-family DUB | • Cleaves Lys63-linked ubiquitin chains from TRAF2, RIPK1 and TAK1 (REF. 28) |
| USP31 | USP-family DUB | • Upstream: cleaves Lys63-linked chains from TRAF2 (REF. 28) • Downstream: cleaves ubiquitin chains from p65 modifying its transcriptional activity28 |
| MCPIP1 | • Unclassified DUB • Inducible by TNF • Interaction with diverse adaptor proteins can instruct MCPIP1 to function as either RNase or DUB |
• Upstream DUB: cleaves Lys63-linked chains from TRAF2 and RIPK1 (REF. 143) • Downstream DUB: cleaves Lys48-linked chains from IκBα143 • RNase: promotes degradation of inflammatory mRNAs144 |
| Itch | • E3 ubiquitin ligase • Interacts with A20 or CYLD to form ubiquitin-editing complexes35,36 |
Conjugates Lys48-linked ubiquitin chains to substrates, inducing their proteasomal degradation35,36 |
| Optineurin | • Antagonistic ubiquitin binder inducible by TNF • Mutations in OPTN have been identified in patients with POAG and ALS29, including ALS-associated mutations that disrupt the ubiquitin-binding capacity of optineurin and abolish its inhibitory functions in TNFR signalling29 |
Antagonizes the binding of NEMO to polyubiquitinated RIPK1 (REFS 29,30) |
| p47 | Antagonistic ubiquitin binder | Binds to polyubiquitinated NEMO directing its lysosomal degradation31 |
| Phosphatases | ||
| PP1 | Phosphatase | • Targets IKK-complex39 • Binding to IKK-complex is directed by the adaptor protein CUEDC2 (REF. 39) |
| PPP2CA-PPP2R1A-PPP2R5C (PP2A holoenzyme) | Phosphatase | Targets TRAF2 |
| PPP2CB-PPP2R1A (PP2A core enzyme) | Phosphatase | Targets IKK-complex |
| PPP2CA-PPP2R1B (PP2A core enzyme) | Phosphatase | Removes Ser536-phosphorylation from p65, modifying its transcriptional activity |
| PP2Cα (PP1A) | Phosphatase | Targets IKK-complex |
| PP2CP (PP1B) | Phosphatase | • Targets TAK1; binding to TAK1 is directed by the adaptor protein 14-3-3E40 • Targets IKK-complex |
| WIP1 (PP1D) | Phosphatase | Removes Ser536-phosphorylation from RelA/p65, modifying its transcriptional activity41 |
| Inhibitors of NFκB | ||
| IκBα | Rapidly inducible by TNF43 | Newly synthesized IκBα enters the nucleus, dissociates NFκB dimers from chromatin, and exports NFκB to the cytoplasm42 |
| IκBε | Inducible by TNF with slower kinetics (compared with IκBα)43,44 | Functions as a back-up or fail-safe mechanism43,44 |
| IκBδ (p100) | Inducible by TNF with delayed and sustained kinetics43 | Sequesters NFκB subunits in cytoplasm |
ABIN, A20-binding inhibitor of NFκB activation; ALS, amyotropic lateral sclerosis; CUEDC2, CUE domain-containing protein 2; DUB, deubiquitinating enzyme; GSK-3β, glycogen synthase kinase 3β; HOIP, HOIL-1-interacting protein (E3 ubiquitin-protein ligase RNF31); IBD, inflammatory bowel disease; IκB, inhibitor of κB; IKK, IκB kinase; LUBAC, linear ubiquitin chain assembly complex; MCPIP1, MCP-induced protein 1 (ribonuclease ZC3H12A); NEMO, NFκB essential modulator; NFκB, nuclear factor κB; OTU, ovarian tumour; POAG, primary open-angle glaucoma; RA, rheumatoid arthritis; RIPK1, receptor-interacting serine/threonine-protein kinase 1; RNF11, RING finger protein 11; SLE, systemic lupus erythematosus; TAK, transforming growth factor (TGF)-β-activated kinase 1; TAX1BP1, Tax1-binding protein 1; TNFR, TNF receptor; TRAF, TNFR-associated factor; USP, ubiquitin specific peptidase.