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.