TNF and Ubiquitination

Abstract

Tumour necrosis factor (TNF) is a potent inflammatory cytokine. TNF is required to fight off infections but is also a crucial player in several pathological conditions including inflammatory bowel disease, psoriasis, rheumatoid arthritis and cancer. TNF‐induced inflammation can be the result of TNF‐induced gene activation but also cell death. TNF can activate gene induction via both of its receptors, TNF receptor 1 and 2 (TNFR1 and TNFR2), but induction of cell death occurs exclusively via TNFR1. Consequently, the TNFR1‐signalling complex (TNFR1‐SC) needs to be regulated which is also achieved by posttranslational modifications. Various components of the signalling complex are phosphorylated and/or ubiquitinated. Ubiquitination is the conjugation of the 7.6‐kDa protein ubiquitin to another protein and has emerged as a crucial posttranslational modification in many signalling pathways. Ubiquitination ensures correct complex formation and disassembly. An intriguing network of ubiquitin ligases, deubiquitinases and ubiquitin‐binding proteins forms a central part of TNFR1 signalling.

Key Concepts

  • TNF, via its receptor TNFR1, can trigger gene activation or cell death.
  • TNF‐induced gene activation and also cell death can drive inflammatory diseases.
  • Ubiquitin chains can be assembled by linking the C‐terminal glycine of ubiquitin to one of the seven lysine (K) residues or methionine 1 (M1) of another ubiquitin.
  • Ubiquitin ligases regulate the signalling complex assembly by attaching ubiquitin chains, composed of different linkage types, to individual complex components.
  • Specific ubiquitin‐binding proteins recognise different ubiquitin linkage types, thus enabling their recruitment to the signalling complex and to act as adaptors.
  • Deubiquitinases can specifically remove certain linkage types in order to regulate the spatiotemporal assembly/disassembly of the signalling complex.
  • Failure to regulate the ubiquitin system in TNFR1 signalling can be causative for excessive inflammation, pathological cell death and autoimmunity.

Keywords: ubiquitin; TNF; ubiquitination; inflammation; LUBAC

Figure 1. Regulation of TNFR1‐mediated gene activation by ubiquitination. Binding of TNF to TNFR1 induces receptor trimerisation at the plasma membrane. Subsequent recruitment of the adaptor molecule TRADD allows for additional recruitment of RIP1 and the ubiquitin ligases TRAF2 and cIAP1/2. Conjugation of K63‐ and K11‐linked ubiquitin chains by cIAP1/2 to several signalling complex components provides a binding platform for ubiquitin‐binding molecules. This includes LUBAC, the TAB/TAK‐ and NEMO/IKK‐complex. LUBAC adds M1‐linked ubiquitin chains to, for example TRADD, RIP1 and TNFR1 which provides complex stability and enables efficient gene activation. Phosphorylation and ubiquitination of RIP1 prevents its engagement in the induction of cell death. While the TAB/TAK‐complex mediates MAPK activation, NEMO/IKK activation leads to phosphorylation of the inhibitory molecule IκBα. This leads to its K48‐ubiquitination by the SCF‐complex. Once IκBα is degraded by the proteasome, the transcription factors p50/p65 can translocate to the nucleus and induce production of inflammatory cytokines, chemokines and antiapoptotic proteins. Among the induced factors are CYLD, A20 and IκBα which facilitate the termination of the signaling in a negative feedback loop.
Figure 2. Regulation of TNF‐induced cell death. Defects in TNFR1‐SC formation can lead to the formation of a cell death‐inducing complex. Ubiquitination by cIAP1/2 and LUBAC provides complex stability and prevents RIP1 from engaging in cell death induction. Similarly, A20 stabilises linear ubiquitin chains, thus preventing cell death. TAK1/IKK‐mediated phosphorylation of RIP1 also prevents cell death independently of the ubiquitination of RIP1. Once the death‐mediating complex is formed, antiapoptotic proteins such as cFLIP can still prevent the execution of apoptosis or necroptosis. Apoptosis proceeds via activation of caspases and therefore inhibits necroptosis, as RIP1 and RIP3 can be cleaved and inactivated by Caspase‐8.
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Further Reading

Harhaj EW and Dixit VM (2012) Regulation of NF‐kappaB by deubiquitinases. Immunological Reviews 246: 107–124.

Kupka S, Reichert M, Draber P and Walczak H (2016b) Formation and removal of poly‐ubiquitin chains in the regulation of tumor necrosis factor‐induced gene activation and cell death. The FEBS Journal 283: 2626–2639.

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Zinngrebe J, Montinaro A, Peltzer N and Walczak H (2014) Ubiquitin in the immune system. EMBO Reports 15: 28–45.

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Kupka, Sebastian, and Walczak, Henning(Apr 2017) TNF and Ubiquitination. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026797]